Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Open accessAbstract
Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the therapeutic challenges and opportunities for the management of NO and ROS in cardiovascular disease.
AI snapshot
Written from a shortened version of the paper’s full text (it is longer than we read).
TL;DR
This review synthesizes the biology of nitric oxide (NO) and reactive oxygen species (ROS) in the cardiovascular system, emphasizing their enzymatic sources, chemistry, and regulation. It argues that classical NO synthase activity is supplemented by reductive nitrite-reduction pathways under hypoxia, and that the same oxidoreductases (NOS, molybdopterin enzymes, globins) can switch between NO and superoxide production depending on oxygen tension, cofactors, and posttranslational modifications.
Key findings
- NO signaling is concentration-dependent: low pM/nM levels activate high-affinity targets such as soluble guanylyl cyclase (sGC) and cytochrome c oxidase; intermediate levels (50–300 nM) activate diverse responses; levels >1 μM cause oxidative, nitrative, and nitrosative stress via peroxynitrite and nitrosating species.
- eNOS is the main contributor to vascular NO: infusion of a competitive eNOS inhibitor into human systemic or coronary circulation decreases basal blood flow by ~25%. eNOS deletion in mice has limited blood pressure effects (compensated by nNOS and prostaglandins) but impairs angiogenesis and wound healing and accelerates atherosclerosis in ApoE−/− mice.
- Under hypoxia, nitrite reduction by heme and molybdopterin proteins supplements NOS-derived NO. Deoxyhemoglobin reduces nitrite with rate constants rising from 0.12 M⁻¹s⁻¹ (T-state) to 6.0 M⁻¹s⁻¹ (R-state); maximal NO generation occurs around 50% Hb oxygen saturation. About half of basal plasma nitrite derives from salivary reduction of dietary nitrate, the other half from oxidation of eNOS-derived NO.
- eNOS uncoupling (from BH4/BH2 imbalance, l-arginine/ADMA imbalance, Zn/S cluster disruption, S-glutathionylation, or Thr495 phosphorylation) shifts the enzyme from NO to superoxide production; peroxynitrite generated can further oxidize BH4, amplifying dysfunction. NOX isoforms differ: NOX1/2/5 generate superoxide, NOX4 and DUOX1/2 produce hydrogen peroxide; NOX2 is generally the main pathological player, while NOX4 appears largely protective.
Methods
- Narrative review article (Physiological Reviews, 2019;99(1):311–379), synthesizing published biochemistry, cell, animal, and human literature on NO and ROS sources and regulation.
- No primary data collection or new experiments; the text reports findings from cited studies, including rate constants, knockout mouse models, and human supplementation trials.
- Organized into sections covering NO generation and vascular function, superoxide/hydrogen peroxide sources, other ROS (peroxynitrite, HOCl, hydroxyl radical), cross-talk between ROS/RNS sources, and therapeutic opportunities.
Limitations
- The authors state that "because of the immense volume of literature in the field, we are sure that many important works are not included in the reference list," and apologize for unintentional omissions.
- The text makes evident several unresolved controversies it reports rather than resolves: the mechanism of erythrocytic NO transport (ATP release, SNO-Hb, vs. nitrite reduction), the role of SNO-Hb in hypoxic vasodilation (questioned by β-93 cysteine KO mice), the mechanism of NOX4 (superoxide vs. hydrogen peroxide), and opposing hypotheses on mitochondrial ROS in pulmonary arterial hypertension.
- Several cited human trials of l-arginine, BH4, and XO inhibitors show heterogeneous or null results, which the review notes limits confidence in those therapeutic strategies.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 833 cited sources checked · 0 supported · 0 flagged
- Findingcitation§ 1. eNOS
Infusion of a competitive inhibitor of eNOS into the human systemic or coronary circulation decreases basal blood flow by approximately 25%.
“For example, the infusion of a competitive inhibitor of eNOS into the human systemic or coronary circulation decreases basal blood flow by ~25%”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingcitation§ 1. eNOS
In the apolipoprotein E knockout atherosclerosis model, addition of eNOS deletion accelerates the atherosclerotic process.
“In the apolipoprotein E (ApoE) knockout (KO) atherosclerosis model, addition of the eNOS deletion accelerates the atherosclerotic process”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [533] source
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- Findingcitation§ 1. eNOS
eNOS−/− mice show impairments in angiogenesis and wound healing.
“However, eNOS−/− mice show impairments in angiogenesis and wound healing”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [563] source
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- Findingcitation§ 1. eNOS
Overexpression of eNOS is detrimental.
“Notably, overexpression of eNOS is also detrimental”
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- Findingcitation§ 1. eNOS
The red blood cell expresses a functional eNOS that contributes in part to systemic blood pressure responses.
“a number of recent studies using chimeric cross bone marrow transplant mouse models have shown that the red blood cell also expresses a functional eNOS that contributes in part to systemic blood pressure responses”
Quote in the paperNot a substantial claim0 of 3 sources checked
- Findingcitation§ 1. eNOS
At least three eNOS residues are susceptible to S-glutathionylation: Cys689, Cys908, and Cys382.
“At least three residues have been shown to be susceptible: Cys689, Cys908 (162), and Cys382 (160)”
- Also stated in: § 3. Other causes of eNOS uncoupling · plain
“At least three residues have been shown to be susceptible of modification: Cys 689, Cys908 (162), and Cys382 (160) (Table 2).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Also stated in: § 3. Other causes of eNOS uncoupling · plain
- Findingreasoning§ 1. eNOS
Bradykinin and Ca2+ ionophores promote Thr495 dephosphorylation and eNOS activation.
“Thus, bradykinin and Ca2+ ionophores promote Thr495 dephosphorylation and eNOS activation.”
Quote in the paperNot a substantial claim - Findingcitation§ 1. eNOS
S-glutathionylation increases eNOS uncoupling and formation of superoxide with diminished NO synthesis activity.
“The reaction increases eNOS uncoupling and the formation of superoxide with diminished NO synthesis activity.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingcitation§ 1. eNOS
In resting endothelial cells, Thr495 is generally phosphorylated.
“In resting endothelial cells, Thr495 is generally phosphorylated”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [297] source
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- Premisenone given§ Abstract
Oxidoreductase systems including NO synthases, molybdopterin enzymes, and hemoglobins can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite.
“The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite.”
Quote in the paperSubstantial claim - Interpretationnone given§ Abstract
Classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia.
“A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Abstract
Generation of sufficient NO levels to regulate the resistance of blood vessels and maintain adequate blood flow is critical to healthy performance of the vasculature.
“The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature.”
- Also stated in: § II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTION · plain
“The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of an adequate blood flow is critical to the healthy performance of the vasculature”
Quote in the paperSubstantial claim - Also stated in: § II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTION · plain
- Premisecitation§ I. INTRODUCTION
Most ROS/RNS molecules, despite being long considered toxic, have been shown to exert important signaling functions.
“It is worth indicating that despite being long considered toxic species, most of these molecules have been shown to exert important signaling functions”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationnone given§ Abstract
Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate NO/ROS production from oxidoreductases and determine the redox balance in health and disease.
“Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease.”
Quote in the paperSubstantial claim - Premisecitation§ I. INTRODUCTION
Intermediate NO levels (50-300 nM) can activate a range of positive and negative responses from wound healing to oncogenic pathways.
“An emerging paradigm proposes that intermediate levels (50–300 nM) can activate a range of positive and negative responses from wound healing to oncogenic pathways”
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- Premisecitation§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTION
Production of NO in basal conditions is largely regulated by the activity of endothelial NOS (eNOS) in the vascular endothelium.
“The production of NO in basal conditions is largely regulated by the activity of endothelial NOS (eNOS) in the vascular endothelium”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTION
The canonical pathways of NO formation rely on the specialized NOS enzymes.
“The canonical pathways of NO formation rely on the specialized NOS enzymes.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation§ I. INTRODUCTION
A number of proteins involved in oxidative processes at basal oxygen levels can become de facto reductases as oxygen is depleted.
“However, a number of proteins that are involved in oxidative processes at basal oxygen levels can become de facto reductases as oxygen is depleted.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 1. eNOS
Calmodulin affinity to eNOS is regulated via phosphorylation of Thr495.
“In turn, CaM affinity to eNOS is regulated via phosphorylation of Thr495.”
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- Interpretationcitation§ I. INTRODUCTION
The biological role of the oxygen-regulated oxidative-to-reductive transition is particularly prominent for heme- and molybdopterin-containing proteins such as hemoglobin, myoglobin, and xanthine oxidase.
“The biological role of this transition is particularly prominent in the case of heme- and molybdopterin-containing proteins such as hemoglobin (Hb), myoglobin (Mb), and xanthine oxidase (XO)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation§ I. INTRODUCTION
Production of adequate NO in the vascular endothelium is critical for regulation of blood flow and vasodilation.
“The production of adequate levels of NO in the vascular endothelium is critical for the regulation of blood flow and vasodilation”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisereasoning§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTION
Only the NOS dimer is able to generate NO catalytically.
“thus, only the dimer is able to generate NO catalytically.”
Quote in the paperNot a substantial claim - Premisecitation§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTION
Nitrite reduction by heme proteins can mediate hypoxic vasodilation and other physiological responses.
“For instance, nitrite reduction by heme proteins can mediate hypoxic vasodilation and other physiological responses”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. eNOS
PYK2 is activated in endothelial cells by angiotensin II, oxidative stress, and insulin.
“This kinase is activated in endothelial cells by several stimuli including angiotensin II, oxidative stress, and insulin”
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- Premisecitation§ 2. Heme proteins
Nitrite-dependent NO generation in vivo catalyzed by Hb and Mb is well documented.
“However, nitrite-dependent NO generation in vivo catalyzed by Hb and Mb is well documented (183, 185, 365, 862, 975); it is very likely that the measurement of this NO generation is due to the fact that the high concentrations of Hb and Mb (in the mM range) can overcome the low efficiency of the nitrite reduction reaction.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. Inorganic nitrite reduction
Dietary polyphenols from sources including cocoa and dealcoholized red wine are linked to improved vascular function.
“Dietary interventions have indicated improved vascular function linked to the consumption of polyphenols from different sources, including cocoa and dealcoholized red wine (60, 168, 225, 417, 834).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. eNOS
eNOS can be modified posttranslationally by S-glutathionylation.
“Recent reports indicate that eNOS can also be modified posttranslationally by S-glutathionylation”
- Also stated in: § 3. Other causes of eNOS uncoupling · hedged
“Recent reports indicate that eNOS can be modified posttranslationally by S-glutathionylation (162).”
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- Also stated in: § 3. Other causes of eNOS uncoupling · hedged
- Interpretationreasoning§ 1. eNOS
Tyr657 phosphorylation effectively inactivates eNOS.
“Thus, Tyr657 phosphorylation effectively inactivates eNOS.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Heme proteins
The scheme of heme protein-mediated nitrite reduction applies to virtually all heme proteins studied to date, including Hb, Mb, Ngb, Cygb, CBS, globin X, plant and cyanobacterial Hb, flavohemoglobin, heme-albumin, cytochrome c, protoglobin, and microperoxidase-11.
“This scheme has been found to apply to virtually all the heme protein–mediated nitrite reduction reactions studied to date, including Hb (248, 447), Mb (247, 862), neuroglobin (Ngb) (932, 945), Cygb (182, 571, 780), cystathionine β-synthase (CBS) (149, 350), globin X (184), plant and cyanobacterial Hb (phytohemoglobins) (905, 946), flavohemoglobin (340), heme-albumin (43), cytochrome c (41), prot”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2. Heme proteins
Competing reactions, namely NO scavenging by ferrous heme and NO dioxygenation, greatly decrease the amount of bioavailable NO generated by reactions of nitrite with heme proteins.
“It should be noted that competing reactions, namely the scavenging of NO by the ferrous heme [rate constants in the order of 1.7 × 107 to 1.5 × 108 M−1s−1 (180, 967), Eq. 6] and the rate of NO dioxygenation [rate constants in the order of 3.4 × 107 to 8.9 × 107 M−1s−1 for mammalian Hb/Mb (264, 341), Eq. 8] greatly decrease the amount of bioavailable NO generated by the reactions of nitrite with he”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 2. Heme proteins
Rate constants for the reaction of Hb with nitrite change from 0.12 M−1s−1 for T-state Hb to 6.0 M−1s−1 for R-state Hb.
“The rate constants for the reaction of Hb with nitrite change from 0.12 M−1s−1 for T-state Hb to 6.0 M−1s−1 for R-state Hb (Table 3) (447).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [447] source
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- Premisecitation§ 1. Inorganic nitrite reduction
Combined use of polyphenols and nitrite appears to have additive effects in vascular protection.
“Combined use of polyphenols and nitrite appears to have additive effects in vascular protection (791).”
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- Interpretationreasoning§ 1. eNOS
The equilibrium between phosphorylated and dephosphorylated Thr495 is mainly modulated by changes in intracellular Ca2+ levels.
“The equilibrium between phosphorylated and dephosphorylated Thr495 is mainly modulated by the changes in intracellular Ca2+ levels.”
Quote in the paperNot a substantial claim - Premisecitation§ 1. Inorganic nitrite reduction
Effects of dietary polyphenols can be in part due to interaction with different enzymatic systems.
“The effects of these dietary components can be, in part, due to the interaction with different enzymatic systems (30, 558, 824), but the link between these compounds and NO formation deserves further investigation (600, 789).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given§ 1. eNOS
Phosphorylation of Tyr657 is catalyzed by proline-rich tyrosine kinase 2 (PYK2).
“The phosphorylation of Tyr657 is catalyzed by proline-rich tyrosine kinase 2 (PYK2).”
Quote in the paperNot a substantial claim - Premisecitation§ 3. Molybdoproteins
Both mARC enzymes can reduce nitrite to NO in a process very sensitive to oxygen-mediated inhibition.
“Both mARC enzymes can reduce nitrite to NO in a process very sensitive to oxygen-mediated inhibition (Table 4) (880).”
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- Premisereasoning§ 2. Formation of S-nitrosothiols
Most routes of S-nitrosothiol formation require formation of the nitrogen dioxide radical intermediate (NO2·).
“Most of these routes require the formation of the nitrogen dioxide radical intermediate (NO2·) (Eqs. 12a, 12b)”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Heme proteins
CBS-mediated reduction of nitrite to NO by the CBS heme has been reported.
“The CBS-mediated reduction of nitrite to NO by the CBS heme has been recently reported (149, 350).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation§ 3. Molybdoproteins
To date, XO is the most relevant nonheme nitrite reductase in vivo.
“To date, XO is the most relevant nonheme nitrite reductase in vivo. Many studies have shown the relevance of XO in mammalian physiology (357, 568, 577, 578, 998).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2. Heme proteins
Cygb can reduce nitrite to NO at rate constants similar or slightly higher than Ngb.
“Cygb can reduce nitrite to NO at rate constants similar or slightly higher than Ngb (182, 571) (Table 3).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. Structure and function of sGC
The activity of sGC itself is compromised in a number of pathological conditions.
“Apart from changes in NO levels or downstream signaling, the activity of sGC itself is compromised in a number of pathological conditions (355, 363, 600, 853, 888, 1022).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. Structure and function of sGC
Activation of sGC by NO leads to an increase in cGMP synthesis of at least two orders of magnitude.
“The activation of sGC by NO leads to an increase in cGMP synthesis of at least two orders of magnitude (895).”
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- Premisecitation§ 1. Structure and function of sGC
The effects of NO in the vasculature at nM/pM concentrations are mainly mediated through activation of the canonical NO receptor sGC.
“The effects of NO in the vasculature at concentrations in the nM/pM range (397) are mainly mediated through the activation of the canonical NO receptor sGC (223, 662, 711, 751).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2. Heme proteins
Accumulating studies demonstrate production of bioavailable NO from incubation of erythrocytes with nitrite.
“Although theoretical calculations suggest that this type of NO escape should be limited, accumulating studies by many research groups now demonstrate the production of bioavailable NO generated from the incubation of erythrocytes with nitrite (185, 196, 883, 975).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2. Heme proteins
Oxygenated Cygb reacts with NO to form nitrate in a NO dioxygenation reaction that scavenges NO.
“In addition, the oxygenated form of Cygb reacts with NO to form nitrate in a NO dioxygenation reaction that scavenges NO (339) (Eq. 8)”
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- Premisecitation§ 3. Molybdoproteins
All four mammalian molybdenum-containing enzymes (XO, AO, sulfite oxidase, and mARC) are able to reduce nitrite at different intrinsic rates.
“Subsequently, several reports have shown that all mammalian Mo-containing enzymes [XO, aldehyde oxidase (AO), sulfite oxidase, and the mitochondrial amidoxime-reducing component (mARC)] are able to reduce nitrite at different intrinsic rates (Table 4) (575, 880, 990).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 3. Molybdoproteins
The molybdopterin cofactor of sulfite oxidase catalyzes nitrite reduction to produce NO.
“Like XO and AO, the molybdopterin cofactor of sulfite oxidase is able to catalyze nitrite reduction to produce NO (Table 4) (990).”
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- Premisecitation§ 2. Heme proteins
Deoxygenated Ngb can reduce nitrite to NO.
“It was recently demonstrated that, as observed with other globins, deoxygenated Ngb can also reduce nitrite to NO (932, 945).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. Heme proteins
In anoxic conditions, eNOS catalyzes nitrite reduction to NO.
“Indeed, in anoxic conditions, eNOS has been shown to catalyze nitrite reduction to NO (970).”
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- Premisenone given§ 2. Heme proteins
Mb catalyzes nitrite reduction to NO in vitro.
“The ability of Mb to catalyze nitrite reduction to NO was first confirmed in vitro.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Formation of S-nitrosothiols
Global kinetic analysis suggests that the main source of NO2· in vivo may be the decomposition of peroxynitrite.
“Global kinetic analysis of the reactions involved suggests that the main source of NO2· in vivo may be the decomposition of peroxynitrite (585).”
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- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
In healthy situations, mitochondrial ROS generation is probably more related to signaling pathways.
“In healthy situations, the generation of ROS by eNOS, mitochondria, or XO is limited, and in the case of mitochondria, it is probably more related to signaling pathways (289, 290).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationnone given§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
There is significant evidence that not only NOXs but also the generation of ROS by uncoupled eNOS, mitochondria, or XO has particular relevance in the origin and development of cardiovascular disease.
“However, there is significant evidence that not only NOXs but also the generation of ROS by uncoupled eNOS, mitochondria, or XO has particular relevance in the origin and development of cardiovascular disease.”
Quote in the paperSubstantial claim- Rests on an assumption: NADPH oxidases (NOXs) are the most important sources of superoxide and hydrogen peroxide generation in the vasculature quantitatively.
- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
The reductase domain of NOX5 includes a CaM-binding motif not found in the NOX1-4 proteins.
“The reductase domain of NOX5 also includes a CaM-binding motif not found in the NOX1–4 proteins.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
When Ca2+ is bound, the EF hands fold over the reductase CaM element to relieve autoinhibition.
“When Ca2+ is bound, the EF hands fold over the reductase CaM element to relieve autoinhibition (63, 944).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
In the human vasculature, the most relevant NOX isoforms appear to be NOX1, NOX2, NOX4, and NOX5.
“In the human vasculature, the most relevant isoforms appear to be NOX1, NOX2, NOX4, and NOX5 (252, 253, 555).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
Generation of superoxide and hydrogen peroxide mediates critical processes such as angiogenesis, hypoxic adaptation, and energy homeostasis.
“Indeed, the generation of superoxide and hydrogen peroxide, among others, has been shown to mediate critical processes such as angiogenesis, hypoxic adaptation, and energy homeostasis (96, 249, 291, 720, 778, 825, 960).”
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- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
The transmembrane domain includes four conserved histidines that serve as binding sites for two heme moieties bound between helices III and V.
“The transmembrane domain includes four conserved histidines that serve as binding sites for two heme moieties bound between helices III and V (288, 613), and the flavoprotein domain binds the cofactor FAD and includes a binding site for NADPH (49, 480, 613, 980).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. Formation of S-nitrosothiols
Recent studies of eNOS−/− mice compared with wild type mice identify a more limited set of S-nitrosated proteins.
“Recent studies of the proteome of eNOS−/− mice compared with wild type mice identify a more limited set of S-nitrosated proteins (125, 378).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
Takac et al. indicates that the E-loop of NOX4 shows notable differences with the other NOX isoforms.
“The mechanism of NOX4 is still controversial, but elegant work by Takac et al. indicates that the E-loop (sequence between helices V and VI) of NOX4 shows notable differences with the other NOX isoforms (925).”
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- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
NOX5 has a similar architecture to NOX1-4 but has an additional N-terminal domain before the transmembrane domain with four EF hand motifs that are responsive to Ca2+.
“NOX5 has a similar architecture but has an additional N-terminal domain before the transmembrane domain with four EF hand motifs that are responsive to Ca2+.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationnone given§ 2. Formation of S-nitrosothiols
Detection of S-nitrosated proteins in the presence of exogenous NO or R-SNO species can lead to nonphysiological S-nitrosation.
“Altogether, it appears that the detection of S-nitrosated proteins in the presence of exogenous NO or R-SNO species can lead to nonphysiological S-nitrosation and more sensitive methods, monitoring protein S-nitrosation levels in vivo are necessary for accurate detection of these modifications.”
Quote in the paperSubstantial claim - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
In healthy situations, the generation of ROS by eNOS, mitochondria, or XO is limited.
“In healthy situations, the generation of ROS by eNOS, mitochondria, or XO is limited, and in the case of mitochondria, it is probably more related to signaling pathways (289, 290).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
NOX2 activation requires p22phox, p47phox, p67phox, p40phox, and Rac1.
“NOX2 activation requires p22phox, p47phox, p67phox, p40phox, and Rac1 (276).”
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- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
Tks4/5, a homolog of NOXO1, regulates NOX4 activity.
“The membrane protein Toll-like receptor 4 (TLR4) has been shown to increase NOX4 activity (86, 724), and Tks4/5, a homolog of NOXO1, also regulates NOX4 activity (231).”
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- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
NOX1 activation requires p22phox, NOX-organizer 1 (NOXO1), NOX-activator 1 (NOXA1), and the GTPase Rac1.
“NOX1 activation requires p22phox, NOX-organizer 1 (NOXO1), NOX-activator 1 (NOXA1), and the GTPase Rac1 (24, 108, 348).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation§ 1. NOX2
Current knowledge about NOX enzymes in the cardiovascular system indicates that NOX2 is usually the main player in the development of pathological conditions.
“The current knowledge about NOX enzymes in the cardiovascular system indicates that NOX2 is usually the main player in the development of pathological conditions and increased NOX2 activity is linked to vascular disease (142, 252, 478).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. NOX2
Some studies have described that endothelial overexpression of NOX2 increases endothelial dysfunction.
“Some studies have described that endothelial overexpression of NOX2 increases endothelial dysfunction (88, 676).”
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The activator protein p47phox can replace NOXO1 in a noncanonical mode of NOX1 activation.
“The activator protein p47phox can replace NOXO1 in a noncanonical mode (61).”
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- Premisecitation§ 1. NOX2
A large number of cytokines and hormones induce NOX2 expression, including angiotensin II, thrombin, and TNF-α.
“A large number of cytokines and hormones have been shown to induce NOX2 expression, including angiotensin II (658, 714, 802), thrombin (725), and TNF-α (275, 964).”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [658] Moncada S, 1991, Pharmacol Rev source
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- cites [275] source
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- Premisecitation§ 1. NOX2
Increased NOX2 activity is linked to vascular disease.
“The current knowledge about NOX enzymes in the cardiovascular system indicates that NOX2 is usually the main player in the development of pathological conditions and increased NOX2 activity is linked to vascular disease (142, 252, 478).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. NOX2
Circulating lipids increase NOX2 production in ECs in vitro.
“Circulating lipids also increase NOX2 production in ECs in vitro (159, 208, 856, 1063).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
A noncanonical mode of NOX2 activation can use NOXO1 instead of p47phox.
“As described for NOX1, a noncanonical mode of activation can use NOXO1 instead of p47phox (927).”
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- Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
Toll-like receptor 4 (TLR4) has been shown to increase NOX4 activity.
“The membrane protein Toll-like receptor 4 (TLR4) has been shown to increase NOX4 activity (86, 724), and Tks4/5, a homolog of NOXO1, also regulates NOX4 activity (231).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. NOX2
Genetic defects in the main constituents of NOX2 can trigger an inability of immune system cells to kill invading bacteria and fungi.
“Genetic defects in the main constituents of NOX2 can trigger an inability of the immune system cells to kill invading bacteria and fungi.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTION
NOX4 appears to be constitutively active in the presence of p22phox without the participation of cytosolic proteins.
“NOX4 appears to be constitutively active in the presence of p22phox without the participation of cytosolic proteins (24, 627).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. NOX2
NOX2 expression has been reported in other cell types including endothelial cells and adventitial fibroblasts.
“NOX2 expression has been also reported in other cell types including endothelial cells and adventitial fibroblasts (376, 382, 657, 714, 715, 736, 876) (FIGURE 9, Table 5).”
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- Premisecitation§ 1. NOX2
In other cases, increased expression of endothelial NOX2 has not been linked to pathological conditions even though increased production of superoxide and macrophage recruitment was observed.
“However, in other cases, an increased expression of endothelial NOX2 has not been linked to pathological conditions even though an increased production of superoxide and macrophage recruitment was observed (243, 443).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. NOX2
NOX2−/− mice are protected against angiotensin II-dependent hypertension.
“The NOX2−/− mice are also protected against angiotensin II–dependent hypertension (151, 988).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. NOX1
NOX1 is found in caveolae and signalosomes of vascular cells.
“NOX1 is found in caveolae and signalosomes of vascular cells (423, 431, 652).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2. NOX1
Increased NOX1 activity is associated with vascular disease.
“Increased NOX1 activity is associated with vascular disease, and studies have shown links between high NOX1 levels and hypertension (1015), diabetes (163, 380, 1003), ischemia/reperfusion injury (479), and coronary artery disease (393).”
Quote in the paperNot a substantial claim - Interpretationcitation§ 1. NOX2
Subsequent progress of the atherosclerotic lesion is dependent on immune cells.
“The current paradigm indicates that macrophage NOX2 is more detrimental in the development of cardiovascular disease (395, 876), with endothelial NOX2 probably involved in the initiation, but not so much in the development of the disease, and a subsequent progress of the atherosclerotic lesion dependent on immune cells (243, 573, 976).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation§ 2. NOX1
These findings indicate a critical role of NOX1-derived superoxide in angiogenesis signaling via PPARα-, AKT-, and ERK1/2-mediated pathways.
“These findings indicate a critical role of NOX1-derived superoxide in angiogenesis signaling via PPARα-, AKT-, and ERK1/2-mediated pathways.”
Quote in the paperNot a substantial claim - Premisecitation§ 1. NOX2
Some reports do not find significant differences in atherosclerosis progression or lesion size with p47phox−/− ApoE−/−.
“The mice combining the mutation of p47phox−/− with ApoE−/− appear to be protected from atherosclerotic lesions (253) compared with ApoE−/− mice (64, 976), although some reports do not find significant differences in atherosclerosis progression or lesion size (443).”
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- Premisecitation§ 2. NOX1
NOX1 expression is activated by several factors including angiotensin II, PDGF, and thrombin.
“NOX1 expression is activated by several factors including angiotensin II, PDGF, and thrombin (382, 492, 630, 695, 999).”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisecitation§ 2. NOX1
Studies have shown links between high NOX1 levels and hypertension, diabetes, ischemia/reperfusion injury, and coronary artery disease.
“Increased NOX1 activity is associated with vascular disease, and studies have shown links between high NOX1 levels and hypertension (1015), diabetes (163, 380, 1003), ischemia/reperfusion injury (479), and coronary artery disease (393).”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisecitation§ 1. NOX2
Use of p47phox−/− as a surrogate for NOX2 deletion is partly limited by the involvement of p47phox in other protein complexes, including noncanonical activation of NOX1 and interaction with protein disulfide isomerase.
“It should be noted that the use of p47phox−/− as a surrogate for the NOX2 deletion is partly limited by the involvement of p47phox in other protein complexes, including not only the noncanonical activation of NOX1, as already mentioned above but also its interaction with protein disulfide isomerase (214, 559).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. NOX1
siRNA against NOX1 or NOXO1 decreased superoxide production and eNOS uncoupling in diabetic mice.
“siRNA against NOX1 or NOXO1 decreased superoxide production and eNOS uncoupling in diabetic mice (1049).”
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- Premisecitation§ 1. NOX2
Mice combining the mutation of p47phox−/− with ApoE−/− appear to be protected from atherosclerotic lesions compared with ApoE−/− mice.
“The mice combining the mutation of p47phox−/− with ApoE−/− appear to be protected from atherosclerotic lesions (253) compared with ApoE−/− mice (64, 976), although some reports do not find significant differences in atherosclerosis progression or lesion size (443).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 2. NOX1
Knockdown of NOX1 can decrease angiogenesis.
“For instance, knockdown of NOX1 can decrease angiogenesis (343), whereas increased NOX1 promotes tumor angiogenesis and growth (582).”
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- Interpretationcitation§ 1. NOX2
Macrophage NOX2 is more detrimental in the development of cardiovascular disease.
“The current paradigm indicates that macrophage NOX2 is more detrimental in the development of cardiovascular disease (395, 876), with endothelial NOX2 probably involved in the initiation, but not so much in the development of the disease, and a subsequent progress of the atherosclerotic lesion dependent on immune cells (243, 573, 976).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 3. NOX4
In the heart, NOX4 has been identified in ECs, cardiomyocytes, and fibroblasts.
“In the heart, NOX4 has been identified in ECs, cardiomyocytes, and fibroblasts (682, 1058).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 3. NOX4
A beneficial effect of NOX4 in ischemia/reperfusion has also been observed.
“A beneficial effect of NOX4 in ischemia/reperfusion has also been observed (989).”
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- Interpretationcitation§ 3. NOX4
NOX4 protective role may be due to its generation of hydrogen peroxide, and not superoxide.
“NOX4 protective role may be due to its generation of hydrogen peroxide, and not superoxide (253).”
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- Premisecitation§ 3. NOX4
NOX4 deletion in the ApoE−/− mouse does not ameliorate diabetes-associated vasculopathy.
“However, NOX4 deletion in the ApoE−/− mouse does not ameliorate diabetes-associated vasculopathy (380).”
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- Interpretationreasoning§ 2. NOX1
Therapies focused on NOX2 can overlook compensatory effects of NOX1 in part by the sharing of a number of regulatory elements that can activate the production of superoxide in both proteins.
“It is important to consider that therapies focused on NOX2 can overlook compensatory effects of NOX1 in part by the sharing of a number of regulatory elements that can activate the production of superoxide in both proteins.”
Quote in the paperSubstantial claim - Interpretationreasoning§ 3. NOX4
Changes in NOX4 activity do not directly impact NO levels.
“As hydrogen peroxide does not scavenge NO, changes in NOX4 activity do not directly impact NO levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Hydrogen peroxide does not scavenge NO.
- Interpretationcitation§ 3. NOX4
The role of NOX4 in vascular biology appears to be generally protective.
“The role of NOX4 in vascular biology appears to be generally protective.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. NOX1
NOX1 deletion limits the blood pressure increase elicited by angiotensin II.
“NOX1 deletion limits the blood pressure increase elicited by angiotensin II, although it is unclear if basal blood pressure levels are reduced (345, 346, 630).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 3. NOX4
Studies with NOX4−/− mice indicate protection from endothelial dysfunction in wild-type mice compared with the NOX4 deletion.
“Studies with NOX4−/− mice indicate protection from endothelial dysfunction in wild-type mice compared with the NOX4 deletion (832).”
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- Premisecitation§ 3. NOX4
Heart-specific NOX4 overexpression has protective effects in the response to chronic load stress in part due to increased HIF1α response and increased angiogenesis.
“Heart-specific NOX4 overexpression has protective effects in the response to chronic load stress in part due to increased HIF1α response and increased angiogenesis (1058).”
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- Interpretationcitation§ 3. NOX4
In general, NOX4 shows protective effects in ApoE−/− mice.
“In general, NOX4 shows protective effects in ApoE−/− mice (194, 229, 230, 379, 552, 838).”
Quote in the paperNot a substantial claim0 of 6 sources checked - Premisecitation§ 3. NOX4
The signaling mechanisms of hydrogen peroxide in ECs lead to the increased activity of eNOS and other enzymes.
“The signaling mechanisms of hydrogen peroxide in ECs (941) lead to the increased activity of eNOS and other enzymes (121, 141, 193, 251, 815, 940).”
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- Premisecitation§ 3. NOX4
NOX4 can modulate the role of VEGF-induced dimerization of CD146 necessary for cell adhesion.
“Consistent with this role of NOX4-derived ROS in angiogenesis (642, 989), it has been shown that NOX4 can modulate the role of VEGF-induced dimerization of CD146 necessary for cell adhesion (1065), and NOX4-derived ROS can induce the reversible glutathionylation of SERCA and increase Ca2+ levels, thus regulating VEGF-signaling cell migration (273).”
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- Premisecitation§ 4. NOX5
Phosphorylation of Ser475, Ser490, Thr494, and Ser498 within the flavoprotein domain increases Ca2+ sensitivity.
“Phosphorylation of Ser475, Ser490, Thr494, and Ser498 within the flavoprotein domain increases Ca2+ sensitivity (463, 717, 718); this phosphorylation is mediated by different kinases, including PKC isoforms (164).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 4. NOX5
In human blood vessels, NOX5 is expressed in ECs and VSMCs.
“In human blood vessels, NOX5 is expressed in ECs and VSMCs (81, 469) (FIGURE 9, Table 5).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. NOX5
NOX5 expression also increases in the human heart after MI.
“NOX5 expression also increases in the human heart after MI (396).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
A similar approach with NOX4 did not result in significant inhibition of NOX4.
“Notably, a similar approach with NOX4 did not result in significant inhibition of NOX4 (200), which suggests a strong interaction between dehydrogenase and transmembrane domains in NOX4 and points out a critical function of the B-loop in this interaction (460), very probably linked to the constitutive activity of this NOX isoform.”
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- Premisecitation§ 4. NOX5
NOX5 appears to modulate proliferation and cell migration processes.
“NOX5 also appears to modulate proliferation and cell migration processes (371, 719).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
The mechanism of action of DPI is based on the reaction with the FAD moiety of the NOX dehydrogenase domain.
“Its mechanism of action is based on the reaction with the FAD moiety of the NOX dehydrogenase domain (699).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Diphenylene iodonium (DPI) is a nonspecific inhibitor of all NOX isoforms.
“Diphenylene iodonium (DPI) (FIGURE 10) is a nonspecific inhibitor of all NOX isoforms (18, 197, 246).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation§ 4. NOX5
Altogether, increased NOX5 activity seems to be involved in a pathological response.
“Altogether, increased NOX5 activity seems to be involved in a pathological response (661).”
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- Premisecitation§ 4. NOX5
The particular architecture of NOX5 indicates a regulation of its activity through Ca2+ levels.
“As indicated above, the particular architecture of NOX5 indicates a regulation of its activity through Ca2+ levels (62, 469).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Most NOX inhibitors have shown poor specificity between isoforms, hampering progress in the field.
“Most of the inhibitors have shown poor specificity between isoforms, hampering the progress in the field (174).”
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- Premisecitation§ 4. NOX5
Expression of NOX5 in VSMCs and in macrophages and monocytes can contribute to the development of atherosclerotic lesions.
“Expression of NOX5 in VSMCs and in macrophages and monocytes can contribute to the development of atherosclerotic lesions (622, 623).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. NOX5
NOX5 expression can be activated by most of the factors that activate other vascular NOX enzymes such as angiotensin II, TNF-α, PDGF, thrombin, and endothelin-1.
“NOX5 expression can be activated by most of the factors that activate other vascular NOX enzymes such as angiotensin II, TNF-α, PDGF, thrombin, and endothelin-1 (81, 660, 681).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
NOX2ds blocks specifically the interaction between NOX2 and p47phox.
“NOX2ds blocks specifically the interaction between NOX2 and p47phox (199).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
DPI is also an inhibitor of many other ROS-producing enzymes, including NOS, mitochondrial complex I and XO.
“Unfortunately, this reaction is general for any flavin-containing protein, which means that DPI is also an inhibitor of many other ROS-producing enzymes, including, but not limited to, NOS, mitochondrial complex I and XO (18).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
The inhibitor shows high specificity toward NOX2.
“The inhibitor shows high specificity toward NOX2 (199).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Apocynin inhibits NOX2 by reacting with cysteine residues in p47phox that appear to be necessary for enzyme assembly.
“Apocynin inhibits NOX2 by reacting with cysteine residues in p47phox that appear to be necessary for enzyme assembly (894).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
NOXA1 docking sequence (NOXA1ds) is a peptide developed to block the interaction between NOX1 and NOXA1.
“NOXA1 docking sequence (NOXA1ds) is a peptide developed to block the interaction between NOX1 and NOXA1.”
Quote in the paperNot a substantial claim - Premisenone given§ 5. Pharmacological regulation of NOX enzymes
The concomitant formation of NO and superoxide can be especially deleterious as both radicals can combine to form peroxynitrite at diffusion-limited rates.
“The concomitant formation of NO and superoxide can be especially deleterious as both radicals can combine to form peroxynitrite at diffusion-limited rates.”
Quote in the paperSubstantial claim - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
ML171 showed off-target effects with the inhibition of serotonin and adrenergic receptors in the micromolar range.
“ML171 showed off-target effects with the inhibition of serotonin and adrenergic receptors in the micromolar range (359).”
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- Premisecitation§ 1. BH4/BH2
BH4 plays a critical role in the catalytic cycle of NOS.
“In addition, BH4 plays a critical role in the catalytic cycle of NOS (87, 204, 377, 904, 933, 1000, 1007).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Peroxynitrite can in turn oxidize BH4 to BH2, further promoting eNOS uncoupling.
“Peroxynitrite can in turn oxidize BH4 to BH2, further promoting eNOS uncoupling (543).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [543] Kwon NS, 1989, J Biol Chem source
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Existing evidence suggests that GSK2795039 inhibits NOX2 through competition with NADPH for the binding site of the NOX2 dehydrogenase domain.
“Existing evidence suggests that GSK2795039 inhibits NOX2 through competition with NADPH for the binding site of the NOX2 dehydrogenase domain (435).”
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- Premisecitation§ 1. BH4/BH2
The binding of the cofactor tetrahydrobiopterin (BH4) is a requisite for NO synthesis by NOS enzymes.
“The binding of the cofactor tetrahydrobiopterin (BH4) is a requisite for NO synthesis by NOS enzymes.”
Quote in the paperSubstantial claim - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Off-target effects for VAS2870, namely nonspecific alkylation of thiols, have been reported.
“Off-target effects for VAS2870, namely nonspecific alkylation of thiols, have been reported (915).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
No off-target effects were detected against a panel of 135 enzymes, including XO and eNOS, for GKT-136901.
“No off-target effects were detected against a panel of 135 enzymes, including XO and eNOS (545).”
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- Premisecitation§ 5. Pharmacological regulation of NOX enzymes
In conditions that promote uncoupling, the heme group is usually the main generator of superoxide species through the formation of a ferrous/oxy complex that decays to ferric heme and superoxide.
“In conditions that promote uncoupling, the heme group is usually the main generator of superoxide species through the formation of a ferrous/oxy complex that decays to ferric heme and superoxide (Eq. 20) (FIGURE 11) (250, 901, 973, 1033).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
The ratio of NADPH to l-citrulline is close to the optimal value of 1.5 molecules of NADPH per l-citrulline (and NO) generated.
“The electrons transferred from NADPH are almost quantitatively used to catalyze l-arginine oxidation, and the ratio of NADPH to l-citrulline is close to the optimal value of 1.5 molecules of NADPH per l-citrulline (and NO) generated (3, 590).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisereasoning§ 5. Pharmacological regulation of NOX enzymes
A number of factors can alter the electron transfer in NOS so the amount of NADPH required to generate NO becomes much larger, largely due to the reduction of molecular oxygen to generate superoxide.
“However, a number of factors can alter the electron transfer in NOS so the amount of NADPH required to generate NO becomes much larger. This is largely due to the reduction of other substrates, usually molecular oxygen, to generate superoxide.”
Quote in the paperNot a substantial claim - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
Initial reports indicated that nNOS had the ability to produce superoxide in a reaction dependent on NADPH and Ca2+/CaM.
“Initial reports indicated that nNOS had the ability to produce superoxide in a reaction dependent on NADPH and Ca2+/CaM (750).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [750] source
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- Premisenone given§ 5. Pharmacological regulation of NOX enzymes
In conditions in which the substrates and cofactors are present in saturating concentrations, NOS enzymes catalyze the synthesis of NO from molecular oxygen and l-arginine with high efficiency.
“In conditions in which the substrates and cofactors are present in saturating concentrations, NOS enzymes catalyze the synthesis of NO from molecular oxygen and l-arginine with high efficiency.”
Quote in the paperNot a substantial claim - Premisenone given§ 1. BH4/BH2
BH4 binding synergistically enhances the affinity toward the substrate l-arginine.
“BH4 binding synergistically enhances the affinity toward the substrate l-arginine.”
Quote in the paperNot a substantial claim - Premisecitation§ 5. Pharmacological regulation of NOX enzymes
The reaction is observed in the three NOS isoforms.
“The reaction is observed in the three NOS isoforms (750, 973, 1034).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given§ 2. l-Arginine/ADMA
The absence of l-arginine leads to the production of superoxide in an otherwise active form of NOS.
“The absence of l-arginine leads to the production of superoxide in an otherwise active form of NOS; thus, l-arginine availability can have an important effect on eNOS uncoupling (Table 6).”
Quote in the paperSubstantial claim - Premisecitation§ 1. BH4/BH2
The conversion of BH4 to BH2 in the setting of endothelial dysfunction has been widely reported.
“The conversion of BH4 to BH2 in the setting of endothelial dysfunction has been widely reported (192, 258, 550).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ 3. Other causes of eNOS uncoupling
Breakdown of the Zn/S cluster is in most cases secondary to eNOS uncoupling.
“The breakdown of the Zn/S cluster is, in most cases, secondary to eNOS uncoupling.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ 2. l-Arginine/ADMA
l-Arginine availability can have an important effect on eNOS uncoupling.
“The absence of l-arginine leads to the production of superoxide in an otherwise active form of NOS; thus, l-arginine availability can have an important effect on eNOS uncoupling (Table 6).”
Quote in the paperSubstantial claim - Premisecitation§ 2. l-Arginine/ADMA
ADMA is mainly produced from the breakdown of proteins containing methylated arginine residues.
“ADMA (FIGURE 3) is mainly produced from the breakdown of proteins containing methylated arginine residues.”
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- Premisecitation§ 2. l-Arginine/ADMA
More recent observations indicate that the ADMA/l-arginine ratios in plasma may be a better marker than either metabolite assessed independently.
“More recent observations indicate that the ADMA/l-arginine ratios in plasma may be a better marker than either metabolite assessed independently (75, 589, 606, 790, 966).”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisecitation§ 1. BH4/BH2
BH4 can be oxidized in vivo by molecular oxygen or ROS to generate dihydrobiopterin (BH2), a pterin unable to support NO synthesis.
“BH4 can be oxidized in vivo by molecular oxygen or ROS to generate dihydrobiopterin (BH2), a pterin very structurally similar to BH4 but unable to support NO synthesis (544, 753, 933).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation§ 1. BH4/BH2
The BH4/BH2 ratio gives a more precise estimation of endothelial function than the relative amount of BH2.
“Thus, rather than the relative amount of BH2, the BH4/BH2 ratio gives a more precise estimation of the endothelial function (190, 192, 974).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 3. Other causes of eNOS uncoupling
The Zn/S cluster is particularly sensitive to peroxynitrite.
“Work by Zou et al. indicated that this cluster is particularly sensitive to peroxynitrite (1070).”
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- Premisereasoning§ 1. BH4/BH2
The accumulation of BH2 becomes deleterious as the binding site of BH4 in NOS can also bind this pterin.
“The accumulation of BH2 becomes deleterious as the binding site of BH4 in NOS can also bind this pterin.”
Quote in the paperSubstantial claim - Premisecitation§ 3. Other causes of eNOS uncoupling
The dimeric structure of NOS is held together by interactions between the oxygenase domains, including formation of a Zn/4S cluster with two cysteines from each NOS monomer.
“The dimeric structure of NOS is held together by interactions between the oxygenase domains, and among these interactions, the formation of a Zn/4S cluster with the participation of two cysteines from each NOS monomer (195).”
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- Premisecitation§ 1. BH4/BH2
iNOS and nNOS show higher affinity toward BH4 than for BH2 (around 10-fold in the absence of l-arginine).
“iNOS and nNOS show higher affinity toward BH4 than for BH2 (around 10-fold in the absence of l-arginine) (6, 514, 753); however, eNOS shows almost identical binding affinities for BH4 and BH2, and it is thus very sensitive to imbalances in the concentrations of BH4 and BH2 (190).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ 3. Other causes of eNOS uncoupling
Zn/S cluster breakdown is not a 100% specific marker of eNOS uncoupling because the superoxide source may be different from NOS, for example, a NOX enzyme.
“Although this is not a 100% specific marker of eNOS uncoupling (the superoxide source may be different from NOS, for example, a NOX enzyme), the correlation of the Zn/S cluster breakdown and eNOS uncoupling is probably elevated (Table 6, FIGURE 12).”
Quote in the paperNot a substantial claim - Interpretationreasoning§ 3. Other causes of eNOS uncoupling
Breakdown of the Zn/S cluster does not increase the rate of superoxide formation.
“The superoxide formation from the monomer is low as compared with the uncoupled dimer, and thus, this mechanism does not increase the rate of superoxide formation.”
Quote in the paperSubstantial claim- Rests on an assumption: Superoxide formation from monomeric eNOS is low compared with the uncoupled dimer.
- Interpretationcitation§ 2. l-Arginine/ADMA
In recent years, it has become clear that extracellular l-arginine and ADMA concentrations, compartmentalization, and membrane transporters are important for NOS function.
“However, in recent years, it has become clear that extracellular l-arginine and ADMA concentrations, compartmentalization, and membrane transporters are important for NOS function, as will be discussed below in sect. IIIB4 (167, 668, 1030).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ 3. Other causes of eNOS uncoupling
Breakdown of the Zn/S cluster is a marker indicating generation of peroxynitrite in the cellular environment.
“However, the breakdown of the Zn/S cluster is a marker that indicates the generation of peroxynitrite in the cellular environment.”
Quote in the paperNot a substantial claim - Premisereasoning§ 3. Other causes of eNOS uncoupling
Oxidation of the cysteine residues involved in Zn/S cluster formation disrupts the NOS dimer structure.
“The oxidation of the cysteine residues involved in the formation of the Zn/S cluster disrupts the dimer structure.”
Quote in the paperSubstantial claim - Premisecitation§ 3. Other causes of eNOS uncoupling
Metal-thiol bonds are among the main targets of peroxynitrite.
“This observation is not unexpected, as metal-thiol bonds are some of the main targets of peroxynitrite (78, 526).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisereasoning§ 3. Other causes of eNOS uncoupling
Monomeric eNOS cannot catalyze the NO synthesis reactions.
“As discussed above, the monomeric eNOS cannot catalyze the NO synthesis reactions, and the monomerization renders the heme group inactive.”
Quote in the paperSubstantial claim - Premisereasoning§ 3. Other causes of eNOS uncoupling
Monomerization renders the eNOS heme group inactive.
“As discussed above, the monomeric eNOS cannot catalyze the NO synthesis reactions, and the monomerization renders the heme group inactive.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. l-Arginine/ADMA
In saturating conditions of the NOS cofactors, the synthesis of NO only requires l-arginine and O2 as substrates.
“In saturating conditions of the NOS cofactors, the synthesis of NO only requires l-Arginine and O2 as substrates (904).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [904] source
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- Interpretationreasoning§ 3. Other causes of eNOS uncoupling
The correlation of Zn/S cluster breakdown and eNOS uncoupling is probably elevated.
“Although this is not a 100% specific marker of eNOS uncoupling (the superoxide source may be different from NOS, for example, a NOX enzyme), the correlation of the Zn/S cluster breakdown and eNOS uncoupling is probably elevated (Table 6, FIGURE 12).”
Quote in the paperNot a substantial claim - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Related pterins, such as folate, can produce effects similar to BH4.
“related pterins, such as folate, can also produce similar effects (32, 33, 860).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Studies assessing coronary artery function in patients with atherosclerosis did not find improvement after BH4 treatment.
“Studies, including the assessment of coronary artery function in patients with atherosclerosis, did not find an improvement after BH4 treatment (1028).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1028] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Acute BH4 improves vasodilatation in healthy individuals and patients with hypertension, hypercholesterolemia, chronic heart failure, coronary artery disease, heart failure with reduced ejection fraction, rheumatoid arthritis, or smokers.
“This effect has been observed in a number of human studies, including healthy individuals (450, 743, 987) and patients with hypertension (429), hypercholesterolemia (318, 899, 1031), chronic heart failure (849), coronary artery disease (618, 850), heart failure with reduced ejection fraction (178), or rheumatoid arthritis (619) or smokers (418, 929, 957).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 3. Other causes of eNOS uncoupling
Thioredoxin has been proposed to deglutathionylate eNOS independently of glutathione oxidation.
“Along with glutaredoxin-1, thioredoxin has also been proposed to deglutathionylate eNOS, and this process is independent of glutathione oxidation (907).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [907] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Uncoupling of eNOS has been noted as a target for therapeutic potential.
“As such, the uncoupling of eNOS has been noted as a target for therapeutic potential (488, 569, 570, 600, 784).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
According to the kindling hypothesis of endothelial dysfunction, initial formation of ROS by other sources can promote uncoupling of NOS, amplifying the initial excess of ROS.
“According to the kindling hypothesis of endothelial dysfunction, the initial formation of ROS by other sources can promote uncoupling of NOS, amplifying the initial excess of ROS (488).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [488] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Sepiapterin supplementation improves endothelial function in several mouse models, including atherosclerosis ApoE−/− mice, diabetes models, and obesity models.
“Sepiapterin supplementation improves endothelial function in several mouse models, including the atherosclerosis model ApoE−/− mice (560), diabetes models (721), or obesity models (527).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Low levels of BH4 are found in endothelial dysfunction and cardiovascular disease.
“Conversely, low levels of BH4 are found in endothelial dysfunction and cardiovascular disease (421, 429, 440, 550, 560, 858, 899).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 3. Other causes of eNOS uncoupling
S-nitrosation of cysteine residues Cys96 and Cys101 disrupts the Zn/S cluster.
“Another modification that disrupts the Zn/S cluster is S-nitrosation of the cysteine residues Cys96 and Cys101, as discussed in sect. IIA1.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites sect. IIA1
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Many studies show that BH4 levels correlate with eNOS activity.
“Many studies have shown that BH4 levels correlate with eNOS activity (796, 1006).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
In patients with hypertension, a 4-8-wk, 400 mg/day BH4 treatment decreased blood pressure.
“In patients with hypertension, a 4–8-wk, 400 mg/day treatment was able to decrease blood pressure (747).”
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- Premisecitation§ 3. Other causes of eNOS uncoupling
Glutathionylation of Cys689 and Cys908 causes eNOS uncoupling.
“The glutathionylation of Cys689 and Cys908 causes eNOS uncoupling.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [162] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Uncoupling causes eNOS activity to change from healthy (producing NO) to toxic (generating superoxide).
“The uncoupling causes eNOS activity to change from healthy (producing NO) to toxic (generating superoxide) (303).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [303] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Treatment with antioxidants improves endothelial function in certain conditions.
“As the treatment with antioxidants has been shown to improve endothelial function in certain conditions (56, 419, 420, 422, 572), it is possible that the coadministration of BH4 with ascorbic acid or other antioxidants can circumvent these issues.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ 4. Pharmacological interventions in eNOS uncoupling
Different treatments may prove more efficacious at different stages as the status of eNOS uncoupling changes with the severity of the cause.
“As the status of eNOS uncoupling changes with the severity of the cause, different treatments may prove more efficacious at different stages (FIGURE 12).”
Quote in the paperSubstantial claim - Premisecitation§ 3. Other causes of eNOS uncoupling
S-glutathionylation of eNOS can be reversed by glutaredoxin-1.
“The process can be reversed by glutaredoxin-1 (160).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [160] source
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- Interpretationnone given§ 4. Pharmacological interventions in eNOS uncoupling
The sensitivity of the eNOS system to oxidative stress converts eNOS into a main target in conditions of ROS imbalance.
“The sensitivity of the eNOS system to oxidative stress converts eNOS into a main target in conditions of ROS imbalance.”
Quote in the paperSubstantial claim - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Acute supplementation of BH4, either orally or injected, generally improves vasodilatation.
“Acute supplementation of BH4, either orally or injected, generally improves vasodilatation.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation§ 3. Other causes of eNOS uncoupling
Increase in ROS levels, BH4 depletion, and glutathione oxidation, with subsequent eNOS S-glutathionylation, appear intimately related.
“Consistent with this view, the increase in ROS levels, BH4 depletion, and glutathione oxidation, with subsequent eNOS S-glutathionylation, appears to be intimately related (189, 215).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
400 mg daily BH4 for 1 wk improved endothelial function in rheumatoid arthritis patients.
“A recent study using 400 mg daily for 1 wk improved endothelial function in rheumatoid arthritis patients (619).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [619] source
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- Premisecitation§ 3. Other causes of eNOS uncoupling
Phosphorylation of Thr495 is a negative regulator of CaM binding to eNOS.
“Phosphorylation of Thr495 is a negative regulator of CaM binding to eNOS (297, 407, 646).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisereasoning§ 4. Pharmacological interventions in eNOS uncoupling
Sepiapterin can be converted into BH4 via the salvage pathway by sepiapterin reductase and dihydrofolate reductase.
“Sepiapterin can be converted into BH4 via the salvage pathway by sepiapterin reductase and dihydrofolate reductase as described in the previous sections.”
Quote in the paperSubstantial claim - Interpretationnone given§ 4. Pharmacological interventions in eNOS uncoupling
In severe oxidative stress conditions, BH4 is rapidly oxidized to BH2, further increasing the BH2/BH4 ratio.
“In severe oxidative stress conditions, the BH4 will be rapidly oxidized to BH2, further increasing the BH2/BH4 ratio (FIGURE 12).”
Quote in the paperSubstantial claim - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
In hypercholesterolemia patients, oral BH4 for 4 wk (400 mg twice daily) improved endothelial function.
“In hypercholesterolemia patients, oral BH4 for 4 wk (400 mg twice daily) improved endothelial function (186).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [186] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Studies on pulmonary hypertension show improvement in the 6-min walking distance with BH4.
“Studies on pulmonary hypertension also show improvement in the 6-min walking distance (788).”
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- Premisenone given§ 4. Pharmacological interventions in eNOS uncoupling
In human patients, l-arginine supplementation results have been heterogeneous.
“Further studies have explored l-arginine supplementation in human patients. Again, the results have been heterogeneous.”
Quote in the paperNot a substantial claim - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
In conditions in which dihydrofolate reductase is inactive or absent, recovery of eNOS coupling by sepiapterin supplementation is ineffective.
“In conditions in which dihydrofolate reductase is inactive or absent, the recovery of eNOS coupling by sepiapterin supplementation is ineffective (452).”
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
High l-arginine levels have been correlated with higher incidence of ischemic heart disease.
“In some cases high, l-arginine levels have even been correlated with higher incidence of ischemic heart disease (1045).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1045] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
In animal models of MI, l-arginine supplementation shows mixed results, with some studies showing improvement in functional recovery and others detrimental outcomes.
“In animal models of MI, l-arginine supplementation shows mixed results. Some studies show improvement in functional recovery (712), whereas studies in l-arginine–treated dogs show detrimental outcomes (665).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Most cells have intracellular l-arginine concentrations manyfold higher than the eNOS KM value.
“This finding was rather surprising, as most cells have intracellular l-arginine concentrations manyfold higher than the eNOS KM value, and thus, this observation has been termed the “arginine paradox” (12, 797).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Overexpression of GCH1 in cells and mouse models improves eNOS function.
“Overexpression of GCH1 in cells and mouse models improves eNOS function (19, 143).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
GCH1 is the rate limiting enzyme during de novo BH4 synthesis.
“To improve endogenous BH4 synthesis, efforts have focused in GCH1, the rate limiting enzyme during de novo BH4 synthesis (143).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [143] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
l-arginine import via the CAT1 transporter is critical for eNOS activity.
“Further studies showed that l-arginine import via the CAT1 transporter is critical for eNOS activity (167, 634).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Folic acid has been shown to prevent nitroglycerin tolerance in short-term human studies.
“Supplementation of folic acid (5-methyltetrahydrofolate) shows positive effects on eNOS function (900, 978) and has been shown to prevent nitroglycerin tolerance in short-term human studies (375).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [375] source
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Most studies detect decreases in blood pressure with l-arginine supplementation.
“In contrast, most studies detect decreases in blood pressure with supplementation.”
Quote in the paperNot a substantial claim - Interpretationcitation§ 4. Pharmacological interventions in eNOS uncoupling
The involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes.
“It seems that the involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes (668, 857, 1029).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Supplementation of folic acid (5-methyltetrahydrofolate) shows positive effects on eNOS function.
“Supplementation of folic acid (5-methyltetrahydrofolate) shows positive effects on eNOS function (900, 978) and has been shown to prevent nitroglycerin tolerance in short-term human studies (375).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
The ratio of l-arginine to ADMA appears to be a better indicator of cardiovascular risk.
“As pointed out above, the ratio of l-arginine to ADMA appears to be a better indicator of cardiovascular risk (28, 103, 104, 606, 1050).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Direct supplementation of l-arginine increases NO production in cells.
“The direct supplementation of l-arginine was shown to increase NO production in cells.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ 4. Pharmacological interventions in eNOS uncoupling
Effects of folic acid on eNOS uncoupling seem related to antioxidant properties of folic acid metabolites.
“The effects on eNOS uncoupling seem related to the antioxidant properties of the folic acid metabolites (900).”
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Other studies show impaired recovery in peripheral artery disease patients with l-arginine.
“Other studies show impaired recovery in peripheral artery disease patients (1014).”
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
A recent meta-analysis indicates that l-arginine doses between 4 and 24 g/day decrease blood pressure (systolic 5 mmHg; diastolic 3 mmHg).
“A recent meta-analysis indicates that doses between 4 and 24 g/day decrease blood pressure (systolic, 5 mmHg; diastolic, 3 mmHg) (240).”
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- Premisecitation§ 2. Physiological role of mitochondrial ROS
Mice completely lacking MnSOD died within weeks of birth.
“Mice completely lacking MnSOD, leading to greater mitochondrial superoxide concentrations, died within weeks of birth (584), confirming the essentiality of mitochondrial superoxide scavenging.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [584] source
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- Premisenone given§ 1. Mechanisms of ROS production
Mitochondrial ROS production is regulated by oxygen levels, substrate availability, and mitochondrial morphology/dynamics, which modulate the redox state of the ETC.
“Mitochondrial ROS production is regulated by a number of factors including oxygen levels, substrate availability, and mitochondrial morphology/dynamics, all of which ultimately modulate the redox state of the ETC.”
Quote in the paperNot a substantial claim - Premisecitation§ 1. Mechanisms of ROS production
Specific complex III inhibitors, such as Antimycin A, can stabilize the semiquinone radical, significantly enhancing superoxide production by complex III.
“Importantly, specific complex III inhibitors, such as Antimycin A, can stabilize this semiquinone radical, significantly enhancing superoxide production by complex III (678).”
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- Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Other studies observed positive effects of l-citrulline including reduced blood pressure.
“Other studies have observed positive effects of l-citrulline including reduced blood pressure (20, 285, 286).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Mitochondria
A small proportion (~2-11%) of electrons entering the ETC escape from the chain at complex I or III to generate superoxide.
“Although the majority of electrons entering the ETC ultimately reduce oxygen to water at complex IV, a small proportion (~2–11%) of electrons escape from the chain at complex I or III to generate superoxide (34, 115, 678).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Studies of l-citrulline in humans show mixed results.
“The studies of l-citrulline in humans show mixed results.”
Quote in the paperNot a substantial claim - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
l-citrulline has been used to increase l-arginine levels.
“For example, l-citrulline has also been used to increase l-arginine levels (842, 1029).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisereasoning§ 2. Physiological role of mitochondrial ROS
These ischemic conditions promote reverse electron transfer upon reperfusion, resulting in significant superoxide production from complex I.
“Together, these conditions promote reverse electron transfer upon reperfusion, which results in significant superoxide production from complex I (171).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [171] source
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- Premisereasoning§ 1. Mechanisms of ROS production
This slow-electron-transport superoxide production occurs in conditions of high NADH/NAD+ ratios, such as low cellular ATP demand or sustained ETC damage.
“This occurs in conditions of high NADH/NAD+ ratios, such as when cellular ATP demand is low or the ETC has sustained damage.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ 1. Mechanisms of ROS production
These non-ETC mitochondrial ROS sources, although lower in capacity, potentially play a role in specific mitochondrial-dependent redox signaling pathways.
“These sources, although lower in their ROS-generating capacity, potentially play a role in specific mitochondrial-dependent redox signaling pathways.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Physiological role of mitochondrial ROS
Mice partially or conditionally lacking MnSOD showed dilated cardiomyopathy characterized by left ventricle dilation, decreased wall thickness, and hypertrophy.
“Further, mice partially or conditionally lacking MnSOD showed dilated cardiomyopathy characterized by left ventricle dilation, decreased wall thickness, and hypertrophy (584, 696).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 4. Pharmacological interventions in eNOS uncoupling
Arginases play an important role in the regulation of l-arginine levels.
“Finally, it must be noted that arginases play an important role in the regulation of l-arginine levels (144, 259, 734, 804).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ 2. Physiological role of mitochondrial ROS
Mitochondrial ROS production plays a major role in the pathogenesis of MI.
“It is now evident that mitochondrial ROS production also plays a major role in the pathogenesis of MI.”
Quote in the paperSubstantial claim - Premisecitation§ 1. Mechanisms of ROS production
eNOS has been shown to enter the mitochondrion of pulmonary smooth muscle cells upon stimulation with asymmetric dimethyl arginine or endothelin-1.
“For example, eNOS has been shown to enter the mitochondrion of pulmonary smooth muscle cells upon stimulation with asymmetric dimethyl arginine or endothelin-1 (768, 916).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisereasoning§ 1. Mechanisms of ROS production
In conditions in which electron transport through the ETC is slow, the FMN center of complex I can become reduced and react with oxygen, catalyzing superoxide production.
“In conditions in which electron transport through the ETC is slow, this FMN can become reduced and react with oxygen, catalyzing superoxide production.”
Quote in the paperNot a substantial claim - Premisecitation§ 1. Mechanisms of ROS production
Complex III-dependent ROS production is important in physiological signaling pathways, including hypoxic sensing.
“However, a number of studies demonstrate that complex III–dependent ROS production is important in physiological signaling pathways, including hypoxic sensing (997).”
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- Premisecitation§ C. Mitochondria
The mitochondrial electron transport chain represents a physiologically significant generator of ROS within vascular cells.
“The mitochondrial electron transport chain (ETC) represents a physiologically significant generator of ROS within vascular cells.”
Quote in the paperNot a substantial claim - Interpretationcitation§ 4. Pharmacological interventions in eNOS uncoupling
l-citrulline supplementation can avoid the formation of detrimental high ADMA levels.
“This supplementation can avoid the formation of detrimental high ADMA levels (632).”
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- Premisecitation§ 1. Mechanisms of ROS production
Reaction of the semiquinone radical with oxygen leads to superoxide production at complex III.
“Although in most cases this semiquinone is rapidly oxidized, its reaction with oxygen leads to superoxide production at this site (567, 678).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. Physiological role of mitochondrial ROS
Specific polymorphisms in the gene for MnSOD have been established as an independent risk factor for coronary artery disease.
“Notably, specific polymorphisms in the gene for MnSOD have been established as an independent risk factor for coronary artery disease (317).”
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- Premisecitation§ 2. Physiological role of mitochondrial ROS
Mitochondrial hydrogen peroxide can oxidize the catalytic subunit of AMP kinase, leading to its autophosphorylation and activation to modulate metabolism.
“Mitochondrial hydrogen peroxide can oxidize the catalytic subunit of AMP kinase, leading to its autophosphorylation and subsequent activation to modulate metabolism within the cell (481, 1067).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given§ 1. ROS generation by XOR
During normal operation, XDH shows limited production of superoxide/hydrogen peroxide via electron leak through the reduced FAD cofactor to O2.
“During normal operation, XDH shows a limited production of superoxide/hydrogen peroxide via electron leak through the reduced FAD cofactor to O2.”
Quote in the paperNot a substantial claim - Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial function
MitoSNO, a mitochondrially targeted S-nitrosothiol, significantly attenuates infarct size after MI in rodent models.
“For example, MitoSNO (FIGURE 14), a mitochondrially targeted S-nitrosothiol, was shown in rodent models to significantly attenuate infarct size after MI (170).”
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- Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial function
MitoSNO protection is dependent on transnitrosating a critical cysteine in the active site of complex I.
“Mechanistically, this protection is dependent on MitoSNO transnitrosating a critical cysteine in the active site of complex I.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [170] source
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- Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial function
The positive charge of triphenylphosphonium is delocalized over its large hydrophobic area, allowing MitoQ to freely be taken into mitochondria based on the mitochondrial membrane potential.
“The positive charge of the triphenylphosphonium cation is delocalized over its large hydrophobic area, which allows it to freely be taken into the mitochondria based on the mitochondrial membrane potential (873).”
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- Premisecitation§ 2. Physiological role of mitochondrial ROS
Mitochondrial ROS have been shown to induce organellar degradation (e.g., mitophagy) under specific conditions.
“As a counterbalance, mitochondrial ROS have also been shown to induce organellar degradation (e.g., mitophagy) under specific conditions (810).”
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- Interpretationnone given§ 2. Physiological role of mitochondrial ROS
Changes in mitochondrial redox status play a role in disease progression.
“Although the role of mitochondrial ROS in pathogenesis remains controversial and a hot area of research, there is no doubt that changes in mitochondrial redox status play a role in disease progression.”
Quote in the paperNot a substantial claim - Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial function
Phase I clinical trials established that SS-31 was safe and well tolerated.
“Phase I clinical trials established that the molecule was safe and well tolerated (360).”
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- Premisecitation§ 2. Physiological role of mitochondrial ROS
Low physiological concentrations of mitochondrial oxidants mediate essential cellular signaling pathways.
“Importantly, although mitochondrial ROS can propagate cellular damage, low physiological concentrations of mitochondrial oxidants have been shown to mediate a number of essential cellular signaling pathways (290).”
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- Interpretationreasoning§ 2. Physiological role of mitochondrial ROS
Mitochondrial ROS potentially play a role as a mediator in feedback pathways to regulate mitochondrial energetics and redox signaling.
“Through these mechanisms, mitochondrial ROS potentially play a role as a mediator in elaborate feedback pathways to regulate mitochondrial energetics and redox signaling.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Physiological role of mitochondrial ROS
A similar pathway exists in the pulmonary vasculature in which mitochondria-generated oxidants signal hypoxic vasoconstriction.
“A similar pathway exists in the pulmonary vasculature in which mitochondria-generated oxidants signal the conserved phenomenon of hypoxic vasoconstriction (995).”
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- Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial function
Chronic hepatitis C patients treated with MitoQ for 28 days showed significant lowering of liver injury markers such as circulating alanine transaminase.
“In contrast, chronic hepatitis C patients treated with MitoQ for 28 days showed significant lowering of liver injury markers such as circulating alanine transaminase (333).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [333] source
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- Interpretationreasoning§ 2. Pharmacological interventions targeting XO
Because of tungsten's mechanism, effects independent of XO will also be observed due to inhibition of AO, sulfite oxidase, and mARC.
“Because of this mechanism of action, it should be noted that effects independent of XO will also be observed because of inhibition of AO, sulfite oxidase, and mARC.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Pharmacological interventions targeting XO
The activity of febuxostat is not impaired by XO immobilization on the surface of ECs.
“Notably, the activity of febuxostat is not impaired by XO immobilization on the surface of ECs (620).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [620] source
Not checked in the free run.
- Premisecitation§ 2. Pharmacological interventions targeting XO
Extensive evidence supports a role of XO in the development of cardiovascular disease.
“Extensive evidence supports a role of XO in the development of cardiovascular disease (137, 148, 157, 282, 430, 466, 561, 633).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ 1. ROS generation by XOR
These changes in substrate affinity lead to increased electron flow from the molybdopterin domain to oxygen instead of NAD+.
“Altogether, these changes in substrate affinity lead to an increased electron flow from the molybdopterin domain to oxygen instead of NAD+.”
Quote in the paperSubstantial claim - Premisecitation§ 2. Pharmacological interventions targeting XO
Tungsten alleviates atherosclerosis in ApoE−/− mice.
“Tungsten is a powerful tool for the study of molybdenum enzymes in cell and animal studies and has been found to alleviate atherosclerosis in ApoE−/− mice (833).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [833] source
Not checked in the free run.
- Premisecitation§ 2. Pharmacological interventions targeting XO
Allopurinol and oxypurinol have limited capacity to inhibit XO bound to glycosaminoglycans.
“It has also been pointed out that allopurinol and oxypurinol have limited capacity to inhibit XO bound to glycosaminoglycans (620).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [620] source
Not checked in the free run.
- Premisecitation§ 2. Pharmacological interventions targeting XO
Subsequent larger trials with allopurinol/oxypurinol failed to report substantial positive effects compared with placebo.
“Despite these initial results, subsequent trials with larger number of patients have failed to report substantial positive effects as compared with the placebo groups (361, 405), although the meta-analysis of available studies indicates some improvement of cardiovascular function (430).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 2. Pharmacological interventions targeting XO
Meta-analysis of available studies indicates some improvement of cardiovascular function with allopurinol/oxypurinol.
“Despite these initial results, subsequent trials with larger number of patients have failed to report substantial positive effects as compared with the placebo groups (361, 405), although the meta-analysis of available studies indicates some improvement of cardiovascular function (430).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [430] source
Not checked in the free run.
- Premisecitation§ 2. Pharmacological interventions targeting XO
Amelioration of endothelial function in smokers was observed with allopurinol/oxypurinol.
“Amelioration of endothelial function in smokers was also observed (387).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [387] source
Not checked in the free run.
- Premisereasoning§ 2. Pharmacological interventions targeting XO
Tungsten can be used as a global inhibitor of molybdenum-containing enzymes as it replaces the Mo atom in molybdopterin, rendering enzymes inactive.
“Tungsten can be used as a global inhibitor of molybdenum-containing enzymes as it replaces the Mo atom in the molybdopterin, rendering the enzymes that use this cofactor inactive.”
Quote in the paperNot a substantial claim - Premisecitation§ 2. Pharmacological interventions targeting XO
In small trials, pharmacological inhibition of XO with allopurinol/oxypurinol improved cardiovascular conditions in heart failure, dilated cardiomyopathy, and diabetes.
“In small trials, the pharmacological inhibition of XO with allopurinol/oxypurinol improved cardiovascular conditions in several pathologies, including heart failure (58, 278), dilated cardiomyopathy (148), and diabetes (137, 224).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. ROS generation by XOR
Oxidation of cysteine residues 535 and 992 in rat or bovine XDH or limited proteolysis turns XDH into XO.
“Oxidation of cysteine residues 535 and 992 in rat or bovine XDH or limited proteolysis turns XDH into XO (23, 72, 693, 773, 803, 994).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 1. ROS generation by XOR
Binding of plasma XO to ECs can lead to vascular dysfunction.
“The binding of plasma XO to ECs can lead to vascular dysfunction (45, 71, 562, 612, 1010).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 2. Pharmacological interventions targeting XO
Studies in rodents have shown improvement in atherosclerosis and hypertension after treatment with febuxostat.
“Studies in rodents have shown improvement in atherosclerosis and hypertension after treatment with febuxostat (697, 859).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. ROS generation by XOR
Low-circulating levels of plasma XO in baseline conditions can increase in disease conditions by release from damaged cells in liver or other tissues.
“There are low-circulating levels of plasma XO in baseline conditions that can increase in disease conditions by the release from damaged cells in liver or other tissues (1010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1010] source
Not checked in the free run.
- Premisecitation§ 1. ROS generation by XOR
XO is expressed in ECs.
“XO is expressed in ECs (393), and its activity is increased by angiotensin II (551), TNF-α, LPS (117, 311), IL-6, and hypoxia (410, 748).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [393] source
Not checked in the free run.
- Premisecitation§ 4. CYPOR and CYP
CYPOR is a diflavin protein structurally and evolutionarily related to the reductase domain of the NOS enzymes.
“CYPOR is a diflavin protein, structurally and evolutionarily related to the reductase domain of the NOS enzymes (377) that functions as a general reductase of the many CYP proteins.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [377] source
Not checked in the free run.
- Premisecitation§ 2. Pharmacological interventions targeting XO
Recent work indicates nitrite treatment can be effective in reducing blood pressure in hypertensive patients.
“Recent work indicates that this treatment can be effective in the reduction of blood pressure in hypertensive patients (357).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [357] source
Not checked in the free run.
- Premisecitation§ 3. AO
The Mo-containing protein AO has been described as a potential source of superoxide in vivo.
“The Mo-containing protein AO has also been described as a potential source of superoxide in vivo (538, 539).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 3. AO
A known single nucleotide polymorphism in the AOX1 gene produces a mutant enzyme with increased superoxide formation rates in vitro.
“However, a known single nucleotide polymorphism in the AOX1 gene was shown to produce a mutant enzyme with increased superoxide formation rates in vitro (304).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [304] source
Not checked in the free run.
- Premisecitation§ 2. Lipoxygenases
Lipoxygenases are biological sources of superoxide.
“Lipoxygenases catalyze the insertion of oxygen in polyunsaturated fatty acids (119, 535, 1040) and are also biological sources of superoxide (537).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [537] source
Not checked in the free run.
- Premisecitation§ 1. Peroxidases and COX
Several studies have correlated low circulating MPO levels with better cardiovascular prognosis.
“Several studies have correlated low circulating MPO levels with better cardiovascular prognosis (239, 260, 644, 690, 1059).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. Peroxidases and COX
Both COX-1 and COX-2 have been related to endothelial dysfunction.
“Two isoforms are expressed in mammals: COX-1 and COX-2, and both of them have been related to endothelial dysfunction (981, 982).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. Peroxidases and COX
Macrophage localization in the atherosclerotic plaque leads to detectable MPO activity and products of HOCl oxidation.
“Macrophage localization in the atherosclerotic plaque leads to detectable MPO activity and products of HOCl oxidation (213, 414).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 3. AO
The human AOX1 isoform is not reactive toward NADH.
“Recent work on the human enzyme shows that the production of superoxide by the human AOX1 isoform is lower than that of the rat enzymes, and the enzyme is not reactive toward NADH (304).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [304] source
Not checked in the free run.
- Premisecitation§ 3. AO
Studies with rat AO have shown a significant production of superoxide when the enzyme uses NADH as a substrate.
“Studies with rat AO have shown a significant production of superoxide when the enzyme uses NADH as a substrate (539).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [539] source
Not checked in the free run.
- Premisecitation§ 3. AO
The production of superoxide by the human AOX1 isoform is lower than that of the rat enzymes.
“Recent work on the human enzyme shows that the production of superoxide by the human AOX1 isoform is lower than that of the rat enzymes, and the enzyme is not reactive toward NADH (304).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [304] source
Not checked in the free run.
- Premisecitation§ IV. OTHER ROS
Peroxynitrite reacts relatively slowly in comparison with other RNS with many biomolecules, including metal centers, proteins, DNA, and lipids.
“Despite its rapid rate of formation, peroxynitrite reacts relatively slowly in comparison with other RNS, with many biomolecules, including metal centers, proteins, DNA, and lipids (78, 526, 709).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 4. CYPOR and CYP
The presence of CYPOR and CYP proteins in endothelial cells makes them a significant source of superoxide in the vasculature.
“The presence of these proteins in endothelial cells makes them a significant source of superoxide in the vasculature (295, 298).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
In the cardiovascular system, peroxynitrite can oxidize heme proteins, such as Hb and Mb, resulting in the oxidation of their heme oxygen-carrying site from ferrous iron to ferric heme.
“In the cardiovascular system, peroxynitrite can oxidize heme proteins, such as Hb and Mb, resulting in the oxidation of their heme oxygen–carrying site from ferrous iron to ferric heme (101, 942).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
Another physiological route by which peroxynitrite can be formed is through the reaction of hydrogen peroxide with nitrite in acidic conditions.
“Another physiological route by which peroxynitrite can be formed is through the reaction of hydrogen peroxide with nitrite in acidic conditions (Eq. 24) (808).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [808] source
Not checked in the free run.
- Premisecitation§ IV. OTHER ROS
Peroxynitrite can directly oxidize reduced glutathione, depleting the antioxidant capacity of the cell.
“In addition to proteins, peroxynitrite can directly oxidize reduced glutathione, depleting the antioxidant capacity of the cell (37).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] source
Not checked in the free run.
- Premisecitation§ 4. CYPOR and CYP
CYPOR, either directly or in combination with the CYP proteins, has been described as a source of superoxide.
“CYPOR, either directly or in combination with the CYP proteins, has been described as a source of superoxide (758, 851).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 5. HO
HO-mediated heme degradation generates ferrous iron (Fe2+) and CO.
“This process generates ferrous iron (Fe2+) and CO, which are well-known toxic species (122, 739, 795, 959), but CO can also be, in low concentrations, a signaling molecule (713, 739, 805, 807).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ IV. OTHER ROS
In the mitochondrion, peroxynitrite oxidizes the electron transport protein cytochrome c.
“In the mitochondrion, a similar reaction oxidizes the electron transport protein cytochrome c (942).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [942] source
Not checked in the free run.
- Interpretationcitation§ IV. OTHER ROS
Peroxynitrite can mediate oxidation/nitration distant from its site of formation.
“Additionally, studies show peroxynitrite can traverse cell membranes by both diffusion and through ion channels, suggesting that peroxynitrite can mediate oxidation/nitration distant from its site of formation (221, 611).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning§ IV. OTHER ROS
Methodology beyond nitrotyrosine measurement is required to confirm the presence of peroxynitrite in biological systems.
“Thus, methodology beyond nitrotyrosine measurement is required to confirm the presence of peroxynitrite in biological systems.”
Quote in the paperSubstantial claim - Premisecitation§ IV. OTHER ROS
Peroxynitrite can traverse cell membranes by both diffusion and through ion channels.
“Additionally, studies show peroxynitrite can traverse cell membranes by both diffusion and through ion channels, suggesting that peroxynitrite can mediate oxidation/nitration distant from its site of formation (221, 611).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. CYPOR and CYP
Some NADPH-dependent superoxide measurements can be unable to differentiate CYPOR from NOX as the source of superoxide because of functional similarities with the dehydrogenase domain of NOX.
“Because of the functional similarities with the dehydrogenase domain of NOX, some NADPH-dependent superoxide measurements can be unable to differentiate CYPOR from NOX as the source of superoxide (783).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [783] source
Not checked in the free run.
- Premisecitation§ 5. HO
CO can be, in low concentrations, a signaling molecule.
“but CO can also be, in low concentrations, a signaling molecule (713, 739, 805, 807).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ IV. OTHER ROS
Reaction of peroxynitrite with Zn/S clusters such as that present in eNOS causes dysfunction of the enzyme.
“Reaction of peroxynitrite with Zn/S clusters such as that present in eNOS, causes dysfunction of the enzyme as outlined above (sect. IIIB3) (78, 526).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
Multiple studies have shown that nitration is a selective process.
“Although a growing number of proteins have now been shown to be nitrated, multiple studies have shown that nitration is a selective process (47, 484).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
Peroxynitrite reacts rapidly with Fe/S clusters leading to the inactivation of critical enzymes such as mitochondrial aconitase.
“Additionally, peroxynitrite reacts rapidly with Fe/S clusters leading to the inactivation of critical enzymes such as mitochondrial aconitase (155, 401).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
Protein nitration can also occur through the reaction of nitrite with heme proteins in the presence of hydrogen peroxide.
“Importantly, protein nitration can also occur through the reaction of nitrite with heme proteins in the presence of hydrogen peroxide (153, 154).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisenone given§ IV. OTHER ROS
Peroxynitrite is a strong oxidizing and nitrating agent formed by the reaction of NO with superoxide.
“Peroxynitrite (ONOO−) is a strong oxidizing and nitrating agent formed by the reaction of NO with superoxide (Eq. 23).”
Quote in the paperNot a substantial claim - Premisecitation§ IV. OTHER ROS
Peroxynitrite-mediated oxidation of ETC components such as complex I and complex V results in inhibition of mitochondrial function.
“For example, peroxynitrite-mediated oxidation of ETC components such as complex I and complex V results in inhibition of mitochondrial function (767).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [767] Rahaman MM, Nguyen AT, Miller MP, Hahn SA, Sparacino-Watkins C, Jobbagy S, Carew NT, Cantu-Medellin N, Wood KC, Baty CJ, Schopfer FJ, Kelley EE, Gladwin MT, Martin E, and Straub AC. Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling. Circulation Research 121: 137–148, 2017. doi:10.1161/CIRCRESAHA.117.310705. source
Not checked in the free run.
- Premisecitation§ IV. OTHER ROS
The oxidation and chlorination of proteins, such as matrix metalloproteinases, leads to detrimental vascular remodeling.
“The oxidation and chlorination of proteins, such as matrix metalloproteinases, leads to detrimental vascular remodeling (314).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [314] source
Not checked in the free run.
- Premisecitation§ IV. OTHER ROS
Tyrosines for which the aromatic ring is closer to the surface of a protein, in which there is a neighboring negative charge, and those in hydrophobic regions are more likely to be nitrated.
“Tyrosines for which the aromatic ring is closer to the surface of a protein, in which there is a neighboring negative charge, and those in hydrophobic regions are more likely to be nitrated (66, 877).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
Peroxynitrite can mediate lipid nitration.
“For example, lipids are also a significant biological target for peroxynitrite, and although the species can abstract a hydrogen atom to initiate lipid peroxidation, a detrimental process that can lead to cytotoxicity in many cases (65, 766), peroxynitrite can also mediate lipid nitration (54, 1027).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. Hydroxyl Radical
In some cases, the reaction may not produce free hydroxyl radical but other metal-based oxidizing species.
“Therefore, in some cases, the reaction may not produce free hydroxyl radical but other metal-based oxidizing species (759, 1020).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
HOCl plays a major role in the microbicidal actions of neutrophils.
“This highly reactive oxidizing and chlorinating agent plays a major role in the microbicidal actions of neutrophils (15, 1021).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ IV. OTHER ROS
HOCl decreases eNOS activity and NO bioavailability by a number of direct and indirect mechanisms, disrupting protective NO signaling.
“Hypochlorous acid decreases eNOS activity and NO bioavailability by a number of direct and indirect mechanisms, disrupting protective NO signaling (2, 464, 1054).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Hydroxyl Radical
In physiology, perhaps the most common source of Fenton chemistry is the presence of increased concentrations of free iron and/or copper.
“In physiology, perhaps the most common source of Fenton chemistry is the presence of increased concentrations of free iron and/or copper (122, 458, 959).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ IV. OTHER ROS
Nitrated fatty acids are a class of electrophilic signaling molecules which have been shown to react with a number of cellular targets to mediate protective inflammatory and metabolic signaling.
“Nitrated fatty acids are a class of electrophilic signaling molecules which have been shown to react with a number of cellular targets to mediate protective inflammatory and metabolic signaling (830).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [830] source
Not checked in the free run.
- Interpretationreasoning§ IV. OTHER ROS
Oxidation of amino acids and metal centers of enzymes results in the HOCl-dependent impairment of a number of critical enzymes.
“Oxidation of amino acids and metal centers of enzymes results in the HOCl-dependent impairment of a number of critical enzymes.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Hydroxyl Radical
The excess of hydrogen peroxide and superoxide in oxidative stress conditions can yield an increased amount of OH·.
“Although the endogenous production of OH· in healthy conditions is apparently negligible (474), the excess of hydrogen peroxide and superoxide in oxidative stress conditions can yield an increased amount of this toxic species (1072).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1072] source
Not checked in the free run.
- Premisecitation§ IV. OTHER ROS
In the context of atherosclerosis, HOCl has been shown to oxidize both high and low density lipoproteins.
“In the context of atherosclerosis, HOCl has been shown to oxidize both high and low density lipoproteins (90, 470, 881, 1042).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ IV. OTHER ROS
Chlorinated proteins and lipids are present in atherosclerotic plaques.
“Furthermore, chlorinated proteins and lipids are present in atherosclerotic plaques (90, 415, 621).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Hydroxyl Radical
The endogenous production of OH· in healthy conditions is apparently negligible.
“Although the endogenous production of OH· in healthy conditions is apparently negligible (474), the excess of hydrogen peroxide and superoxide in oxidative stress conditions can yield an increased amount of this toxic species (1072).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [474] Josephson RA, 1991, J Biol Chem source
Not checked in the free run.
- Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
A direct role of mitochondrial ROS on XO activation has been described.
“A direct role of mitochondrial ROS on XO activation has also been described (362).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [362] source
Not checked in the free run.
- Premisecitation§ C. Hydroxyl Radical
Proteins like ceruloplasmin, transferrin, or lactoferrin limit the Fenton reaction.
“Proteins like ceruloplasmin, transferrin, or lactoferrin limit the reaction (388, 1020).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
Recent work indicates that normalizing a disease state by direct inhibition of a single source of oxidative stress can be a feasible approach.
“Recent work indicates that this can be a feasible approach (206, 207, 234, 836).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. Nitrogen dioxide
Other formation routes of NO2· include the reactions of nitrite with oxygenated Hb and peroxynitrite decomposition.
“Other formation routes include the reactions of nitrite with oxygenated Hb (501) and peroxynitrite decomposition (46).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationnone given§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIES
Oxidation of BH4 by superoxide triggers eNOS uncoupling with decreased NO production and increased superoxide production.
“Different examples of species interaction have been discussed throughout this review; for instance, the oxidation of BH4 by superoxide will trigger eNOS uncoupling with decreased NO production and increased superoxide production.”
Quote in the paperSubstantial claim - Premisecitation§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIES
The use of antioxidants has been markedly ineffective when not damaging.
“The use of antioxidants has been markedly ineffective when not damaging (97, 390, 400, 785).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
Increased ROS eventually causes eNOS uncoupling via BH4 depletion, Zn/S cluster breakdown, and other routes, further perpetuating the generation of superoxide and other ROS.
“As discussed in previous section, increased ROS eventually causes eNOS uncoupling via BH4 depletion, Zn/S cluster breakdown, and other routes, further perpetuating the generation of superoxide and other ROS (FIGURE 17) (488, 570).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
Mitochondrial uncoupling and increased ROS generation activates the mitochondrial permeability transition pore (mPTP), allowing the release of ROS to the cytosol.
“Mitochondrial uncoupling and increased ROS generation activates the mitochondrial permeability transition pore (mPTP), allowing the release of ROS to the cytosol (1069).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1069] source
Not checked in the free run.
- Interpretationreasoning§ C. Hydroxyl Radical
The lack of specificity of OH· makes the use of antioxidants to prevent hydroxyl radical toxicity impractical.
“This lack of specificity makes the use of antioxidants to prevent hydroxyl radical toxicity impractical.”
Quote in the paperNot a substantial claim - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
Current research has advanced knowledge on how different systems can influence NO/ROS generation from other sources, termed ROS-induced ROS release.
“Current research has greatly advanced our knowledge on how different systems can influence the NO/ROS generation from other sources in which it has been termed ROS-induced ROS release (1066, 1069).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
The increase of mitochondrial ROS production after angiotensin II-induced activation of NOX appears to require the function of mitochondrial ATP-dependent potassium channels (KATP).
“This process appears to require the function of mitochondrial ATP-dependent potassium channels (KATP), as shown by the ability of KATP inhibitors to block the increase of mitochondrial ROS production after angiotensin II–induced activation of NOX (242, 507).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
The blockade of mitochondrial ROS by rotenone was shown to prevent NOX1 activation.
“The blockade of mitochondrial ROS by rotenone was shown to prevent NOX1 activation (FIGURE 17) (564).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [564] source
Not checked in the free run.
- Premisecitation§ 2. Dinitrogen trioxide
The formation of N2O3 in the red blood cell via an anhydrase reaction involving Hb, NO, and nitrite constitutes a possible pathway to preserve NO bioactivity.
“As discussed previously in section IIB2, the formation of N2O3 in the red blood cell via an anhydrase reaction involving Hb, NO, and nitrite (69) constitutes a possible pathway to preserve NO bioactivity (367).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
Activated NOX can increase ROS production by the mitochondria.
“Indeed, activated NOX can in turn, increase ROS production by the mitochondria (11, 116).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
In physiological systems, there is not a rigorous separation of roles for each protein or enzymatic system.
“Our description of sources of NO and ROS may give the impression of a rigorous separation of roles for each protein or enzymatic system. This is certainly not the situation in physiological systems.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCES
Mitochondria and NOX are the main effectors of downstream signaling to other sources and to each other.
“Mitochondria and NOX are the main effectors of downstream signaling to other sources and to each other.”
Quote in the paperSubstantial claim - Premisecitation§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIES
The generation of NO through NOS enzymes and oxidative pathways in normoxic conditions is supplemented by the actions of reductive, nitrite-dependent pathways in hypoxia.
“The generation of NO through NOS enzymes and oxidative pathways in normoxic conditions is supplemented by the actions of reductive, nitrite-dependent pathways in hypoxia (603, 968).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationnone given§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIES
Studies on purified protein systems have provided insights on the reactivity of most proteins involved in NO and ROS biology that have been widely validated in vivo.
“The studies on purified protein systems, although necessarily simplistic, have provided insights on the reactivity of most proteins involved in NO and ROS biology that have been widely validated in vivo.”
Quote in the paperNot a substantial claim - Premisecitation§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIES
Mitochondria are a physiologically significant source of ROS with important implications in physiology, not only in cardiovascular disease but in many other conditions like aging.
“Mitochondria are a physiologically significant source of ROS with important implications in physiology, not only in cardiovascular disease but in many other conditions like aging (57, 84, 136, 165, 170, 290, 864, 997).”
Quote in the paperNot a substantial claim0 of 3 sources checked
- Classified as probably not a substantial claim. 74
- May combine two claims. 174
Classified as probably not a substantial claim.
Findingnone given§ I. INTRODUCTIONInitial attempts to enhance NO levels using NO donors or supplementing with NOS substrates to reverse endothelial dysfunction have had limited success.
“For instance, initial attempts to enhance NO levels using NO donors or supplementing with NOS substrates to reverse endothelial dysfunction have had limited success.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Findingnone given§ I. INTRODUCTIONThe use of general antioxidants for the treatment of oxidative stress has failed in most cases.
“The use of general antioxidants for the treatment of oxidative stress has also failed in most cases.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingcitation§ 1. eNOSeNOS deletion has limited effects on mouse blood pressure and vasodilation, as adaptive processes increase production of nNOS and prostaglandins.
“eNOS deletion has some limited effects on mouse blood pressure and vasodilation, as adaptive processes increase the production of nNOS and prostaglandins”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone given§ 1. eNOSVEGF, insulin, and estrogens promote Ser1177 phosphorylation via Akt kinase.
“VEGF, insulin, and estrogens promote Ser1177 phosphorylation via Akt kinase.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone given§ 1. eNOSShear stress activates Ser1177 via PKA-dependent phosphorylation.
“Shear stress activates Ser1177 via PKA-dependent phosphorylation.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingcitation§ 1. eNOSMutation of Tyr657 causes complete loss of NO synthesis and l-citrulline formation, suggesting a blockade of intramolecular electron transfer.
“The mutation of Tyr657 (292) causes complete loss of NO synthesis and l-citrulline formation, suggesting a blockade of the intramolecular electron transfer.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [292] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone given§ 1. eNOSIn resting cells, Ser1177 is usually not phosphorylated.
“In resting cells, Ser1177 is usually not phosphorylated.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ AbstractNO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes.
“NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ I. INTRODUCTIONNO functions in mammalian systems extend beyond vascular signaling and are relevant in all organ systems, including neuronal signaling and host defense.
“The functions of NO in mammalian systems extend beyond vascular signaling and are relevant in all organ systems, including but not limited to neuronal signaling, and host defense”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone given§ I. INTRODUCTIONDysregulated production of ROS/RNS, as is the case for NO, leads to oxidative stress and deleterious consequences for living systems.
“In general, dysregulated production of ROS/RNS, as is the case for NO, leads to oxidative stress and deleterious consequences for living systems.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ I. INTRODUCTIONLow NO levels (pM/nM) are physiological and related to activation of high-affinity primary binding targets such as soluble guanylyl cyclase and cytochrome c oxidase.
“It has been shown that low levels (pM/nM) are physiological and related to the activation of high affinity primary binding targets such as soluble guanylyl cyclase (sGC) and cytochrome c oxidase”
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Interpretationreasoning§ I. INTRODUCTIONThe role of many ROS/RNS molecules in health and disease is related to their production rates, steady-state concentrations, and the ability of cellular antioxidant systems to modulate their activity.
“Therefore, the role of many of these molecules in health and disease is related to their production rates, steady-state concentrations, and the ability of the cellular antioxidant systems to modulate their activity.”
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Premisenone given§ AbstractReactive oxygen species (ROS), including superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism.
“At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ I. INTRODUCTIONHigher NO concentrations (>1 μM) can lead to oxidative stress and nitrative and nitrosative stress via peroxynitrite and nitrosating species, and in combination with oxygen can trigger posttranslational modification of proteins, lipids, and DNA.
“Higher concentrations of NO (>1 μM) can lead not only to oxidative stress but also nitrative and nitrosative stress via the generation of peroxynitrite and nitrosating species”
- Also stated in: § I. INTRODUCTION · plain
“and in combination with oxygen, can trigger posttranslational modification of proteins, lipids, and DNA”
Quote in the paperNot a substantial claim0 of 3 sources checked- Also stated in: § I. INTRODUCTION · plain
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Interpretationnone given§ AbstractDysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and a target for therapy.
“The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ AbstractNitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology.
“Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ 1. eNOSPhosphorylation of Thr495 impairs calmodulin binding, thus blocking Ca2+/calmodulin-dependent activation of eNOS.
“Thr495 is located in the CaM-binding site of eNOS, and the phosphorylation of Thr495 impairs CaM binding, thus blocking Ca2+/CaM-dependent activation of the enzyme”
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Interpretationcitation§ 1. eNOSErythrocyte eNOS can contribute to endocrine NO signaling to modulate blood pressure and myocardial injury and appears tonically regulated by arginase through availability of l-arginine.
“This erythrocyte eNOS can contribute to endocrine NO signaling to modulate both blood pressure and myocardial injury and appears to be tonically regulated by arginase through the availability of the eNOS substrate l-arginine”
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Premisecitation§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTIONNOS are dimeric, multidomain enzymes that synthesize NO from molecular oxygen and l-arginine and use heme, tetrahydrobiopterin, FAD, FMN, and NADPH as cofactors.
“NOS are dimeric, multidomain enzymes that synthesize NO from molecular oxygen and l-arginine and use iron protoporphyrin-IX (heme), tetrahydrobiopterin (BH4), FAD, flavin mononucleotide (FMN), and NADPH as cofactors”
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Premisenone given§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTIONNOS enzymes comprise three main isoforms: nNOS (NOS I), iNOS (NOS II), and eNOS (NOS III).
“NOS enzymes comprise three main isoforms: nNOS (NOS I), iNOS (NOS II), and eNOS (NOS III).”
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Premisereasoning§ 1. eNOSActivation of eNOS requires Ca2+ and calmodulin, but changes in resting Ca2+ concentrations are not strictly necessary to regulate NO synthesis by eNOS.
“The activation of eNOS requires Ca2+ and CaM; however, changes in resting Ca2+ concentrations are not strictly necessary to regulate NO synthesis by eNOS.”
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Interpretationcitation§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTIONeNOS is the enzyme most abundant in vascular endothelial cells and has the most significant impact on vascular function, with a variety of pathologies related to eNOS dysfunction.
“Among these isoforms, eNOS is the enzyme more abundant in vascular endothelial cells and has the most significant impact on vascular function, with a variety of pathologies related with eNOS dysfunction.”
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Premisereasoning§ I. INTRODUCTIONNOSs produce NO using l-arginine and molecular oxygen as substrates, so under hypoxic or anoxic conditions NO generation via NOS is compromised.
“For example, nitric oxide synthases (NOSs) produce NO using l-arginine and molecular oxygen (O2) as substrates. Thus, under hypoxic or anoxic conditions, the generation of NO via NOS is compromised.”
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Interpretationnone given§ 1. eNOSBasal NO produced by eNOS regulates blood flow and tonically inhibits platelet activation and expression of inflammatory adhesion molecules on endothelium.
“Basal levels of NO produced by eNOS not only regulate blood flow but tonically inhibit platelet activation and the expression of inflammatory adhesion molecules on endothelium.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationcitation§ I. INTRODUCTIONOxygen levels can impact the oxidation/reduction properties of different proteins and regulate NO levels.
“In this context, it has become increasingly appreciated that oxygen levels can impact the oxidation/reduction properties of different proteins and regulate NO levels”
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Premisecitation§ II. NITRIC OXIDE GENERATION AND VASCULAR FUNCTIONnNOS and iNOS can provide compensatory NO generation or exacerbated RNS synthesis.
“neuronal NOS (nNOS) and inducible NOS (iNOS) can provide compensatory NO generation or exacerbated RNS synthesis”
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Premisecitation§ 1. eNOSeNOS is the constitutive NOS form in endothelial cells and the main contributor to vascular NO levels in physiological conditions.
“eNOS is the constitutive NOS form in endothelial cells (ECs), and as such, it is the main contributor to vascular NO levels in physiological conditions”
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Premisecitation§ 1. eNOSeNOS is constitutively expressed, and posttranslational modifications impact its ability to produce NO, from changes in NO production rates to complete blockade of NO synthesis.
“eNOS is constitutively expressed; a number of posttranslational modifications impact the ability of eNOS to produce NO, from changes in the NO production rates to, in some cases, the complete blockade of NO synthesis”
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Premisecitation§ 2. Heme proteinsDeoxyHb reduces nitrite, generating nitrosyl Hb and methemoglobin, consistent with electron transfer from ferrous Hb to nitrite.
“Initial reports by Brooks demonstrated that deoxyHb reacts with nitrite, generating nitrosyl Hb and methemoglobin, consistent with electron transfer from a ferrous Hb to nitrite (124).”
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Premisereasoning§ 2. Heme proteinsMathematical modeling of the reaction of Hb with nitrite at different oxygen tensions yields a bell-shaped dependence of observed rates versus oxygen concentration, with maximal NO generation around 50% Hb oxygen saturation, consistent with experimental data.
“In fact, the reaction of Hb with nitrite has been modeled mathematically at different oxygen tensions. The combination of a faster rate at higher oxygen, but increased availability of deoxyHb at low oxygen, leads to bell-shaped dependence of the observed rates versus the oxygen concentration with the maximal rates of NO generation around 50% Hb oxygen saturation, consistent with experimental data”
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Premisecitation§ 2. Heme proteinsThe reaction of deoxyHb with nitrite shows an increase in instantaneous rate as the reaction progresses due to a T-state to R-state shift; NO binds unreacted deoxyHb to stabilize the R-state (R-state autocatalysis).
“The reaction of deoxyHb with nitrite shows an increase in the instantaneous reaction rate as the reaction progresses (447). Studies with T-state and R-state Hb–stabilizing compounds have unambiguously identified the reason for this change is the shift from T-state to R-state during the course of the reaction, as the NO formed in the reaction binds to the unreacted deoxyHb to stabilize the R-state.”
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Premisecitation§ 1. eNOSThr495 phosphorylation is attributed to protein kinase C and the residue is dephosphorylated by protein phosphatase 1.
“The phosphorylation has been attributed to protein kinase C (PKC) (297, 646), and the residue is dephosphorylated by protein phosphatase 1 (PP1)”
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Premisenone given§ 1. eNOSTyr657 is located in the FMN domain of eNOS in close proximity to the FMN cofactor.
“Tyr657 is located in the FMN domain of eNOS in close proximity to the FMN cofactor.”
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Premisecitation§ 1. eNOSSer1177 is located in the C-terminal portion of eNOS in a helical C-terminal tail element that blocks flavin reduction and regulates the conformational equilibrium of the reductase domain.
“Ser1177 is located in the C-terminal portion of eNOS in a helical C-terminal tail element that blocks flavin reduction and regulates the conformational equilibrium of the reductase domain”
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Premisecitation§ 2. Heme proteinsThe reaction of nitrite with deoxyHb requires a proton and formally requires nitrous acid, making it faster at low pH.
“By studying the same reaction using alkyl nitrites, which do not show a pH dependence in their reaction rates with deoxyHb, it was established that the reaction of nitrite requires a proton and thus formally requires nitrous acid (247, 248). This property also makes the reaction faster in low pH conditions.”
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Premisecitation§ 1. eNOSSer1177 phosphorylation activates electron flow through the reductase domain and increases NO synthesis in functional eNOS.
“Ser1177 phosphorylation activates electron flow through the reductase domain and, hence, increases NO synthesis in functional eNOS.”
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Premisecitation§ 2. Heme proteinsThe reaction of two deoxyHb molecules with nitrite yields one nitrosyl Hb and one methemoglobin, with pH critically influencing the process.
“The studies by Huang et al. (445) confirmed the overall stoichiometry of two molecules of deoxyHb generating one molecule of nitrosyl Hb and one molecule of methemoglobin (Eq. 7), consistent with electron transfer from a ferrous Hb to nitrite and indicated the critical influence of pH in the process.”
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Premisecitation§ 3. MolybdoproteinsAO reduces nitrite to NO, albeit at a slower rate than XO.
“AO has been shown to reduce nitrite to NO, albeit a slower rate than XO (Table 4) (568, 575, 617, 1001).”
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Premisecitation§ 2. Heme proteinsHuman studies show a significant gradient of nitrite from arterial to venous circulation, concomitant with production of NO detected as iron-nitrosyl Hb in the venous circulation.
“With regards to the nitrite reduction hypothesis, human studies show a significant gradient of nitrite from the arterial to venous circulation, concomitant with the production of NO (detected as iron-nitrosyl Hb) in the venous circulation (185, 369).”
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Premisecitation§ 2. Heme proteinsIn a murine myocardial infarction model, nitrite decreases infarct size, and this effect is lost in Mb KO mice, which cannot reduce nitrite to NO.
“In a murine myocardial infarction (MI) model, nitrite has been shown to decrease infarct size, and this effect was lost in Mb KO mice, which cannot reduce nitrite to NO (774).”
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Premisenone given§ 1. S-nitrosation and vascular functionAlthough activation of sGC is considered the predominant mechanism of NO-dependent signaling, posttranslational modification of cysteine residues by S-nitrosation comprises a significant alternative mechanism of NO signaling.
“Although activation of sGC is considered the predominant mechanism of NO-dependent signaling, it is now recognized that posttranslational modification of cysteine residues by S-nitrosation comprises a significant alternative mechanism of NO signaling.”
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Premisecitation§ 1. S-nitrosation and vascular functionPhysiological S-nitrosation of specific cysteine residues of RyR2 activates the protein and contributes to maintenance of healthy excitation-contraction coupling.
“Although the RyR2 contains many surface-exposed thiols, physiological S-nitrosation of specific cysteine residues activate the protein and contribute to maintainance of healthy excitation contraction coupling (1038).”
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Premisecitation§ 2. Pharmacological regulation of sGCsGC activators trigger catalytic activity independently of the redox state of the sGC heme or even in the absence of bound heme, working as heme analogs that replace the heme group and activate cGMP formation.
“sGC activators are compounds that can trigger the catalytic activity of sGC independently of the redox state of the sGC heme or even in the absence of bound heme. In general, these compounds work as heme analogs, replacing the heme group and triggering a similar conformational change to that of NO-bound heme in the native enzyme, thus activating cGMP formation (302).”
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Premisecitation§ 1. Structure and function of sGCThe sGC heme group shows high selectivity toward NO, can bind CO weakly, but shows no affinity toward molecular oxygen.
“Remarkably, unlike most other hemoproteins that bind oxygen, CO and NO, this heme group shows a high selectivity toward NO and can also bind CO weakly but shows no affinity toward molecular oxygen (625).”
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Premisecitation§ 2. Heme proteinsA genetic murine model with β93 cysteine replaced by alanine, abolishing SNO-Hb formation, showed no impairment in hypoxic vasodilation, questioning the role of SNO-Hb in physiologic hypoxic vasodilation.
“Additionally, a genetic murine model in which the cysteine 93 of β-Hb was replaced with alanine (and in which SNO-Hb formation was abolished) demonstrated no impairment in hypoxic vasodilation, questioning the role of SNO-Hb in physiologic hypoxic vasodilation (454).”
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Premisenone given§ 2. Formation of S-nitrosothiolsFormation of S-nitrosothiols requires significant concentrations of NO and usually the presence of superoxide and/or peroxynitrite.
“Altogether, we want to note that the formation of the S-nitrosothiols is a complex process, and existing evidence indicates the requirement of significant concentrations of NO and usually the presence of superoxide and/or peroxynitrite.”
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Premisecitation§ 1. S-nitrosation and vascular functionGSNOR catalyzes the denitrosation of glutathione and thus regulates the equilibrium of S-nitrosation.
“The best characterized enzyme in this class is S-nitrosoglutathione reductase (GSNOR), a member of the aldehyde dehydrogenase enzyme group, which catalyzes the denitrosation of glutathione and thus regulates the equilibrium of S-nitrosation (592).”
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Premisecitation§ 2. Heme proteinsThere is consensus that NO-erythrocytic interactions regulate vascular function, particularly that oxygen desaturation of red blood cell Hb stimulates increased vascular NO bioavailability, leading to NO-dependent hypoxic vasodilation.
“There is consensus in the field that NO-erythrocytic interactions regulate vascular function, particularly that oxygen desaturation of red blood cell Hb stimulates increased vascular NO bioavailability, leading to NO-dependent hypoxic vasodilation (266).”
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Premisenone given§ 2. Formation of S-nitrosothiolsNO is not a nitrosating species and does not react directly with thiols.
“However, it should be noted that NO is not a nitrosating species and does not react directly with thiols.”
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Premisecitation§ 2. Heme proteinsInfusions of physiological nitrite concentrations mediate vasodilation in humans, enhanced during exercise and not affected by NOS inhibition, accompanied by iron-nitrosyl Hb formation.
“Consistent with these experiments, infusions of physiological nitrite concentrations mediate vasodilation in humans, which is enhanced during exercise and not affected by NOS inhibition. This effect is accompanied by iron-nitrosyl Hb formation, consistent with nitrite reductase chemistry (185).”
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Premisereasoning§ 2. Formation of S-nitrosothiolsTransnitrosation allows formation of GSNO or S-nitrosated proteins to mediate formation of other S-nitrosothiols and probably serves as a reservoir for S-nitrosothiols in the cellular environment.
“Transnitrosation is a fundamental reaction of S-nitrosothiols and allows for the formation of GSNO or S-nitrosated proteins to mediate the formation of other S-nitrosothiols and probably serve as a reservoir for S-nitrosothiols in the cellular environment.”
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Premisenone given§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONNOX isoforms are regulated by a large number of protein/protein interactions, and most isoforms are not functional without the assembly of the NOX protein with several additional proteins.
“NOX isoforms are regulated by a large number of protein/protein interactions, and most isoforms are not functional without the assembly of the NOX protein with several additional proteins.”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONNOX1-4 are associated with another membrane component, p22phox.
“NOX1–4 are associated to another membrane component, p22phox (24).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONExcess superoxide or other ROS in the cell causes modification of different parts of the cellular machinery and is a known player in the genesis and progression of cardiovascular disease.
“The excess of superoxide, or other ROS, in the cell causes the modification of different parts of the cellular machinery and is a known player in the genesis and progression of cardiovascular disease (227, 408, 409, 570, 672, 700, 893).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONNOX core subunits 1-4 are structurally similar with an N-terminal membrane domain and a C-terminal flavoprotein dehydrogenase domain with high sequence homology to the ferredoxin/NADP reductase family.
“NOX core subunits 1–4 are structurally similar with a N-terminal, membrane domain and a C-terminal flavoprotein, dehydrogenase domain with high sequence homology to the ferredoxin/NADP reductase family (490).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONNADPH is the preferred substrate for all NOX isoforms, with the NOX2 isoform being particularly NADPH specific.
“NADPH is the preferred substrate for all NOX isoforms, with the NOX2 isoform being particularly NADPH specific (48, 63, 177, 1047).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONThe crystal structure of NOX5 has been determined and is consistent with the presence of six transmembrane α helices with five connecting loops.
“Recently, the crystal structure of a NOX core subunit (NOX5) has been determined (613). This structure is consistent with previous evidence suggesting the presence of six transmembrane α helices with five connecting loops (FIGURE 7) (613).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONThe E-loop in NOX4 seems to provide steric hindrance to slow down superoxide release, forcing two superoxide molecules to react with each other in a reaction catalyzed in part by a histidine residue.
“This loop in NOX4 seems to provide steric hindrance to slow down superoxide release, forcing two superoxide molecules to react with each other in a reaction that appears to be catalyzed, in part, by a histidine residue (925).”
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Interpretationreasoning§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONExisting evidence suggests that the primary species generated is superoxide in all isoforms, and the formation of hydrogen peroxide is mediated by the peroxidase-like domain in DUOX or by the dismutation of superoxide molecules in NOX4.
“Existing evidence suggests that the primary species generated is superoxide in all isoforms, and the formation of hydrogen peroxide is mediated by the peroxidase-like domain in DUOX or by the dismutation of superoxide molecules in NOX4 (Eq. 22).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONNOXs are multiprotein enzyme complexes that catalyze the electron transfer to molecular oxygen to form ROS, more commonly superoxide, but also hydrogen peroxide.
“NOXs are multiprotein enzyme complexes that catalyze the electron transfer to molecular oxygen to form ROS, more commonly superoxide, but also hydrogen peroxide (79, 252, 383, 546, 912).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONThe reaction of NOX1-3 and 5 generates superoxide, whereas NOX4 and DUOX1/2 produce hydrogen peroxide.
“Notably, the reaction of NOX1–3 and 5 generates superoxide, whereas NOX4 and DUOX1/2 produce hydrogen peroxide (26, 936).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONDUOX1 and 2 have a similar architecture to NOX5 and include an additional transmembrane domain connected to a putative extracellular peroxidase domain.
“DUOX1 and 2 have a similar architecture to NOX5 and include an additional transmembrane domain connected to a putative extracellular peroxidase domain (262).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONThe flavoprotein domain binds the cofactor FAD and includes a binding site for NADPH.
“The transmembrane domain includes four conserved histidines that serve as binding sites for two heme moieties bound between helices III and V (288, 613), and the flavoprotein domain binds the cofactor FAD and includes a binding site for NADPH (49, 480, 613, 980).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONThe protein polymerase delta-interacting protein 2 (poldip2) seems to exert regulatory effects on NOX4.
“The protein polymerase delta–interacting protein 2 (poldip2) seems to exert regulatory effects on NOX4 (212, 607), although poldip2 is involved on many other pathways (316).”
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Premisecitation§ III. SUPEROXIDE AND HYDROGEN PEROXIDE GENERATION AND VASCULAR FUNCTIONGene splicing appears to modulate NOX4 activation and play important roles in cardiovascular disease.
“In addition, gene splicing also appears to modulate NOX4 activation and play important roles in cardiovascular disease (971).”
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Premisecitation§ 1. NOX2NOX2 is the main NOX isoform in neutrophils and macrophages where it mediates the oxidative burst.
“NOX2 is the main NOX isoform in neutrophils and macrophages where it mediates the oxidative burst (198, 845).”
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Premisecitation§ 1. NOX2Most mutations causing chronic granulomatous disease (around 90%) are found in the membrane component NOX2 and the interacting protein p47phox.
“Most mutations causing the disease (around 90%) are found in the membrane component NOX2 (also known historically as gp91phox) and the interacting protein p47phox.”
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Premisecitation§ 1. NOX2Mice carrying NOX2 deletion treated with high fat diet gain weight but show no increase in ROS production or endothelial dysfunction compared with control animals.
“In these studies, mice carrying the deletion gain weight but show no increase in ROS production or endothelial dysfunction as compared with the control animals (256, 609).”
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Interpretationcitation§ 1. NOX2Endothelial NOX2 is probably involved in the initiation, but not so much in the development of cardiovascular disease.
“The current paradigm indicates that macrophage NOX2 is more detrimental in the development of cardiovascular disease (395, 876), with endothelial NOX2 probably involved in the initiation, but not so much in the development of the disease, and a subsequent progress of the atherosclerotic lesion dependent on immune cells (243, 573, 976).”
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Premisecitation§ 2. NOX1NOX1 is expressed in VSMCs and in lower levels is also found in ECs.
“The isoform NOX1 is expressed in VSMCs and in lower levels is also found in ECs (556, 909) (FIGURE 9, Table 5).”
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Premisecitation§ 2. NOX1NOXA1 has been associated with atherosclerotic injury, with overexpression of NOXA1 increasing ROS production and increased NOXA1 levels detected in atherosclerotic lesions.
“NOXA1 has been also associated with atherosclerotic injury, with overexpression of NOXA1 increasing ROS production and increased NOXA1 levels detected in atherosclerotic lesions (695).”
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Premisecitation§ 1. NOX2The combination of NOX2−/− with ApoE−/− can decrease atherosclerotic lesions, but this is not always the case.
“The combination of NOX2−/− with ApoE−/− can decrease the atherosclerotic lesions (475), but this is not always the case (508).”
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Premisecitation§ 1. NOX2Deletion of the organizer subunit p47phox ameliorates the hypertensive response to angiotensin II, decreases endothelial superoxide formation and eNOS uncoupling, and improves survival after MI.
“The deletion of the organizer subunit p47phox ameliorates the hypertensive response to angiotensin II, decreases endothelial superoxide formation and eNOS uncoupling, and improves survival after MI (238, 549, 550).”
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Premisecitation§ 2. NOX1Increased NOX1 promotes tumor angiogenesis and growth.
“For instance, knockdown of NOX1 can decrease angiogenesis (343), whereas increased NOX1 promotes tumor angiogenesis and growth (582).”
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Premisecitation§ 2. NOX1Overexpression of NOX1 in VSMCs increases blood pressure and hypertrophy in mouse hypertension models.
“In agreement with these observations, the overexpression of NOX1 in VSMCs increases blood pressure and hypertrophy in mouse hypertension models (235).”
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Premisecitation§ 3. NOX4One study has related NOX4 to hyperglycemia and insulin resistance in mice.
“One study has related NOX4 to hyperglycemia and insulin resistance in mice (1012).”
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Premisecitation§ 3. NOX4Other regulators of NOX4 include TNF-α, hypoxia, and PDGF.
“Other regulators include TNF-α (70, 681, 884, 1048), hypoxia (455), and PDGF (487).”
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Premisecitation§ 3. NOX4Endothelial-specific overexpression of NOX4 in mice promotes angiogenesis and eNOS function.
“Endothelial-specific overexpression of NOX4 in mice promotes angiogenesis and eNOS function (193) and decreases blood pressure (779).”
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Premisecitation§ 3. NOX4NOX4 is the most abundant isoform in ECs, and it is also present in VSMCs and adventitial fibroblasts.
“NOX4 is the most abundant isoform in ECs, and it is also present in VSMCs and adventitial fibroblasts (10, 265, 736, 832, 876, 1036).”
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Premisecitation§ 2. NOX1The effect of NOX1 in atherosclerosis is contradictory, with examples of improved outcomes for NOX1 deficient mice subjected to high fat diet and diabetic mouse models, whereas in other cases NOX1 deletion did not seem to have an effect.
“The results of different studies are contradictory, with examples of improved outcomes for NOX1 deficient mice subjected to high fat diet (854) and diabetic mouse models (380), whereas in other cases, NOX1 deletion did not seem to have an effect (875).”
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Interpretationcitation§ 2. NOX1The role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models.
“Altogether, the role of NOX1 in cardiovascular disease seems secondary to NOX2, but still significant, as shown in several models (345, 380, 630, 854).”
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Premisecitation§ 3. NOX4Endothelial-targeted overexpression of NOX4 has beneficial effects and decreases blood pressure.
“Endothelial-targeted overexpression of NOX4 has beneficial effects and decreases blood pressure (779).”
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Premisecitation§ 3. NOX4Splicing of NOX4 appears to influence cardiovascular disease, with a shorter protein (NOX4D) exerting beneficial signaling functions in the nucleus, whereas full-length NOX4 is overexpressed in ischemia with detrimental effects.
“For instance, splicing of NOX4 appears to influence cardiovascular disease, with a shorter protein (NOX4D) exerting beneficial signaling functions in the nucleus, whereas full-length NOX4 is overexpressed in ischemia with detrimental effects (971).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesApocynin is an antioxidant and scavenger of ROS like HOCl and hydrogen peroxide.
“Moreover, there are several factors that question the inhibitory effects of apocynin; notably, apocynin is an antioxidant and scavenger of ROS like HOCl and hydrogen peroxide (426, 735).”
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Premisecitation§ 4. NOX5NOX5 is the last discovered NOX isoform.
“NOX5 is the last discovered NOX isoform (62).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesML171 inhibits NOX1 at nanomolar concentrations, with IC50 values at least 20-fold higher for NOX2, NOX3, NOX4, and XO.
“ML171 inhibits NOX1 at nanomolar concentrations, with IC50 values at least 20-fold higher for NOX2, NOX3, NOX4, and XO (359).”
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Premisenone given§ 5. Pharmacological regulation of NOX enzymesApocynin is a methoxy-substituted catechol generally considered to be a specific NOX2 isoform inhibitor.
“Apocynin (FIGURE 10) is a methoxy-substituted catechol generally considered to be a specific NOX2 isoform inhibitor.”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesNOX2 docking sequence-tat (NOX2ds-tat) is the first isoform-specific NOX inhibitor, a peptide based on the sequence of the B-loop of NOX2.
“NOX2 docking sequence-tat (NOX2ds-tat), the first isoform-specific NOX inhibitor, is a peptide based on the sequence of the B-loop of NOX2 (199, 218, 782).”
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Premisecitation§ 4. NOX5Higher NOX5 expression levels have been observed in patients with coronary artery disease, but causation has not been proven.
“Higher NOX5 expression levels have been observed in patients with coronary artery disease (391), but causation has not been proven.”
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Premisecitation§ 3. NOX4NOX4-derived ROS can induce the reversible glutathionylation of SERCA and increase Ca2+ levels, thus regulating VEGF-signaling cell migration.
“Consistent with this role of NOX4-derived ROS in angiogenesis (642, 989), it has been shown that NOX4 can modulate the role of VEGF-induced dimerization of CD146 necessary for cell adhesion (1065), and NOX4-derived ROS can induce the reversible glutathionylation of SERCA and increase Ca2+ levels, thus regulating VEGF-signaling cell migration (273).”
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Premisecitation§ 3. NOX4Although NOX4 activity has been shown to reduce fibrosis in atherosclerosis, it can also promote fibrosis, particularly in the lung, but also in kidney and other tissues.
“In a final note, it should be also considered that although NOX4 activity has been shown to reduce fibrosis in atherosclerosis (230), it can also promote fibrosis, particularly in the lung, but also in kidney and other tissues (110, 201, 416, 596, 820).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesThe peptide prevents NOX1 assembly and does not inhibit NOX2, NOX4, or NOX5 as tested in in vitro assays.
“The peptide prevents NOX1 assembly and does not inhibit NOX2, NOX4, or NOX5 as tested in in vitro assays (772, 792).”
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Premisecitation§ 4. NOX5Unlike the rest of the NOX proteins, NOX5 does not have a homolog in rodents, which has hampered the research of this isoform.
“Unlike the rest of the NOX proteins, NOX5 does not have an homolog in rodents, which has hampered the research of this isoform (871).”
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Interpretationreasoning§ 5. Pharmacological regulation of NOX enzymesConditions that increase the monomer/dimer ratio decrease NO output and can increase superoxide production through the reductase domain but also decrease superoxide formation in the oxygenase domain.
“Thus, conditions that increase the monomer/dimer ratio decrease NO output and can increase superoxide production through the reductase domain but also decrease superoxide formation in the oxygenase domain (FIGURE 11).”
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Interpretationreasoning§ 5. Pharmacological regulation of NOX enzymesVAS2870 and VAS3947 do not have a noticeable effect on XO- or eNOS-dependent ROS production, so they can be considered specific pan-NOX inhibitors.
“These inhibitors do not have a noticeable effect on XO- or eNOS-dependent ROS production, so they can be considered specific pan-NOX inhibitors.”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesNO production is critical for vascular function.
“NO production is critical for vascular function as described in previous sections (299, 573, 600, 786).”
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Interpretationreasoning§ 5. Pharmacological regulation of NOX enzymesMeasurement of dimer/monomer ratios as an indication of eNOS uncoupling is not a reliable and reproducible method, and more specific methods monitoring posttranslational modifications and substrate levels are preferable.
“Therefore, it should be noted that measurement of dimer/monomer ratios as an indication of eNOS uncoupling is not a reliable and reproducible method, and more specific methods monitoring posttranslational modifications and substrate levels are preferable.”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesPeroxynitrite is a strong oxidant and nitrosating species.
“Peroxynitrite is a strong oxidant and nitrosating species (78).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesVAS2870 appears to inhibit all isoforms, with proven inhibitory effects at least for NOX1, NOX2, NOX4, and NOX5 isoforms.
“VAS2870 appears to inhibit all isoforms, with proven inhibitory effects at least for NOX1, NOX2, NOX4, and NOX5 isoforms (21, 520).”
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Premisenone given§ 5. Pharmacological regulation of NOX enzymesThe loss of the dimer structure renders eNOS unable to produce NO, as the heme group of one monomer must receive electrons from the FMN domain of the other monomer.
“The loss of the dimer structure renders eNOS unable to produce NO, as the heme group of one monomer must receive electrons from the FMN domain of the other monomer.”
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Interpretationcitation§ 5. Pharmacological regulation of NOX enzymesSuperoxide generated by uncoupled eNOS acts as a NO scavenger, decreasing NO availability, and generates peroxynitrite.
“Therefore, the superoxide generated by the uncoupled eNOS not only induces toxic effects on its own but 1) acts as a NO scavenger, decreasing NO availability and 2) generates peroxynitrite, a more harmful species (78).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesGKT-136901 and GKT-137831 are the first inhibitors suitable for oral administration, and currently GKT-137831 is in phase 2 clinical trials.
“GKT-136901 and GKT-137831 (FIGURE 10) are the first inhibitors suitable for oral administration, and currently GKT-137831 is in phase 2 clinical trials (472).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesGKT-137831 shows similar inhibitory properties with potent inhibition of NOX1 and NOX4 and inhibitory effects on NOX2 and NOX5 at higher concentrations.
“GKT-137831 shows similar inhibitory properties with potent inhibition of NOX1 and NOX4 and inhibitory effects on NOX2 and NOX5 at higher concentrations (35).”
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Premisecitation§ 1. BH4/BH2Other pterins are, in general, unable to support NO synthesis in mammalian NOS enzymes, or can only support a NO synthesis rate much slower than BH4.
“Other pterins are, in general, unable to support NO synthesis in mammalian NOS enzymes, or can only support a NO synthesis rate much slower than BH4 (753).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesGKT-136901 was first characterized as a selective NOX1 and NOX4 inhibitor, although it can also inhibit NOX2 at higher concentrations.
“GKT-136901 was first characterized as a selective NOX1 and NOX4 inhibitor, although it can also inhibit NOX 2 at higher concentrations (545).”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesGSK2795039 appears to be specific toward NOX2 and does not show off-target effects toward eNOS or XO.
“GSK2795039 (FIGURE 10) appears to be specific toward NOX2 and does not show off-target effects toward eNOS or XO.”
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Premisecitation§ 5. Pharmacological regulation of NOX enzymesSuperoxide can be generated by the oxygenase/heme domain, in a Ca2+/CaM-dependent way, or independently by the reductase domain from Ca2+/CaM.
“Superoxide can be generated by the oxygenase/heme domain, in a Ca2+/CaM-dependent way, or independently by the reductase domain from Ca2+/CaM (653, 1032).”
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Premisecitation§ 1. BH4/BH2When NOS binds BH2 instead of BH4, the ferrous/oxy heme cannot hydroxylate l-arginine to NG-hydroxy-l-arginine, NO synthesis is blocked, and the oxygen is eventually oxidized to superoxide.
“Mechanistically, when NOS binds BH2 instead of BH4, the ferrous/oxy heme cannot hydroxylate l-arginine to NG-hydroxy-l-arginine, NO synthesis is blocked, and the oxygen is eventually oxidized to superoxide.”
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Premisecitation§ 2. l-Arginine/ADMAADMA was recognized as an important marker for cardiovascular disease progression soon after its discovery in cells and tissue.
“Soon after its discovery in cells and tissue, ADMA was recognized as an important marker for cardiovascular disease progression (656, 829, 961, 1011, 1053, 1068).”
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- cites [829] Schröder H, 1988, J Pharmacol Exp Ther source
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- cites [1011] source
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- cites [1053] source
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Premisecitation§ 1. BH4/BH2eNOS shows almost identical binding affinities for BH4 and BH2, and is thus very sensitive to imbalances in the concentrations of BH4 and BH2.
“iNOS and nNOS show higher affinity toward BH4 than for BH2 (around 10-fold in the absence of l-arginine) (6, 514, 753); however, eNOS shows almost identical binding affinities for BH4 and BH2, and it is thus very sensitive to imbalances in the concentrations of BH4 and BH2 (190).”
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Interpretationreasoning§ 1. BH4/BH2When NOS binds BH2 instead of BH4, not only is NO synthesis completely abolished but the protein also becomes an oxidase, generating superoxide instead of NO.
“Thus, not only is the NO synthesis completely abolished but the protein also becomes an oxidase, generating superoxide instead of NO (191, 972, 1007) (Table 6).”
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Premisecitation§ 2. l-Arginine/ADMAl-Arginine is important for the dimerization of NOS and increases BH4 binding affinity.
“l-Arginine is also important for the dimerization of NOS (51, 515) and increases BH4 binding affinity (514, 753).”
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Premisecitation§ 2. l-Arginine/ADMAADMA and NG-monomethyl-l-arginine (but not symmetric dimethylarginine) are NOS inhibitors and can be important regulators of NOS activity in vivo.
“Notably, ADMA and NG-monomethyl-l-arginine (but not symmetric dimethylarginine) are NOS inhibitors and can be important regulators of NOS activity in vivo (566, 963).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingOral BH4 for 2-6 wk in patients with coronary artery disease did not show improvement and increased BH2 levels.
“A treatment with oral BH4 for 2–6 wk in patients with coronary artery disease did not show improvement; and actually increased BH2 levels (202).”
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Interpretationreasoning§ 4. Pharmacological interventions in eNOS uncouplingSupplementation of BH4 or positive modifications in BH4 synthesis pathways have generally been positive.
“Spearheaded by these observations, interventions to reverse eNOS uncoupling via BH4 supplementation have been numerous, and in general, the supplementation of BH4 or positive modifications in the BH4 synthesis pathways have been positive.”
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Interpretationcitation§ 3. Other causes of eNOS uncouplingCys689 and Cys908 are located in the reductase domain and appear to disturb electron transfer between FAD and FMN cofactors, indirectly limiting the rate of reduction of the oxygenase domain.
“These residues, located in the reductase domain, appear to disturb the electron transfer between FAD and FMN cofactors, and indirectly limit the rate of reduction of the oxygenase domain.”
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Premisecitation§ 3. Other causes of eNOS uncouplingS-glutathionylation is involved in angiotensin II-mediated endothelial dysfunction and nitroglycerin resistance.
“S-glutathionylation has been involved in the development of angiotensin II–mediated endothelial dysfunction (328) and nitroglycerin resistance (522).”
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Interpretationcitation§ 4. Pharmacological interventions in eNOS uncouplingIn most examples, BH4 improves endothelial function, but in some conditions BH4 supplementation is not a practical therapeutic approach.
“In most examples, BH4 is able to improve endothelial function, but the study by Cunnington et al. (202) clearly indicated that in some conditions, BH4 supplementation is not a practical therapeutic approach.”
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Interpretationreasoning§ 3. Other causes of eNOS uncouplingAccumulation of electrons in the reductase domain causes increased uncoupling from the reductase domain, which is less pronounced than in the heme but can cause significant superoxide production.
“The accumulation of electrons in the reductase domain causes an increased uncoupling from the reductase domain, which, as discussed previously, is less pronounced than when this occurs in the heme but can cause significant production of superoxide (Table 6).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingPleiotropic effects of some drugs can improve BH4 availability; this has been observed for statins such as atorvastatin.
“Pleiotropic effects of some drugs can improve BH4 availability; this has been observed for statins such as atorvastatin (31).”
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Premisecitation§ 3. Other causes of eNOS uncouplingThr495-phosphorylated NOS shows decreased electron transfer from the reductase domain to the heme domain and decreased NO synthesis.
“The Thr495-phosphorylated NOS shows decreased electron transfer from the reductase domain to the heme domain and decreased NO synthesis (588).”
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Premisecitation§ 3. Other causes of eNOS uncouplingAddition of l-NAME decreases superoxide production only in part, indicating that most superoxide production occurs in the reductase domain via electron transfer from reduced FAD and FMN to molecular oxygen.
“Consistent with this hypothesis, the addition of the inhibitor l-NAME decreases superoxide production only in part, indicating that most of the superoxide production occurs in the reductase domain via electron transfer from the reduced FAD and FMN to molecular oxygen (162) (Table 6, Figs. 11, 12).”
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Interpretationreasoning§ 3. Other causes of eNOS uncouplingAngiotensin II-mediated endothelial dysfunction and nitroglycerin resistance appear to be initiated by mitochondrial ROS.
“Both processes appear to be initiated by mitochondrial ROS.”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingFolic acid supplementation in human blood vessel samples increases BH4 levels and BH4/BH2 ratios.
“Folic acid supplementation studies in human blood vessel samples have shown increases in BH4 levels and BH4/BH2 ratios (33).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingA membrane metabolon including arginine succinate lyase, argininosuccinate synthetase, hsp90, and eNOS associates in caveolae and is necessary for regular eNOS function.
“A membrane metabolon including arginine succinate lyase, argininosuccinate synthetase, hsp90, and eNOS associates in the caveolae and is necessary for regular eNOS function (270, 294, 634).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingFolic acid has wide effects on metabolism, impacting cysteine/homocysteine metabolism and pathways involving tetrahydrofolate and dihydrofolate and hence BH4 biosynthesis.
“Folic acid has wide effects on the metabolism, impacting cysteine/homocysteine metabolism, but also pathways involving tetrahydrofolate and dihydrofolate and hence BH4 biosynthesis (598).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingMany studies report lack of effect of l-arginine on endothelial function markers, and sometimes l-arginine supplementation is associated with higher mortality after MI.
“Many studies have reported a lack of effect on l-arginine in endothelial function markers, and on occasion, the supplementation of l-arginine has been associated with higher mortality effects, such as tests of l-arginine in patients after MI (835).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingAvailability of l-arginine may be jeopardized under endothelial dysfunction, and concentrations of inhibitory l-arginine metabolites such as ADMA can increase in pathological conditions.
“Several lines of evidence indicate that the availability of l-arginine may be jeopardized under endothelial dysfunction, and the concentrations of inhibitory l-arginine metabolites, such as ADMA, can also increase in pathological conditions (107, 1053).”
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Interpretationreasoning§ 4. Pharmacological interventions in eNOS uncouplingThe sepiapterin salvage pathway has BH2 as an intermediate, which could lead to detrimental effects.
“It should be noted that this pathway has BH2 as an intermediate, which could lead to detrimental effects.”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingStudies of a panel of l-arginine metabolites indicate some correlations, particularly for ADMA, but also the need to consider other factors such as age, sex, and body mass index.
“Studies of a panel of l-arginine metabolites indicate some correlations, particularly for ADMA, but also the need to consider other factors such as age, sex, and body mass index (75, 771).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingMouse GCH1 KO mice show abolished endothelial NO synthesis and increased superoxide production that can be reversed by sepiapterin supplementation.
“Mouse GCH1 KO mice show abolished endothelial NO synthesis and increased superoxide production that can be reversed by sepiapterin supplementation (173).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingHuman variants of GCH1 show measurable effects in blood pressure, indicating a direct relationship between GCH1 and eNOS function.
“Human variants of GCH1 show measurable effects in blood pressure, indicating the direct relationship between GCH1 and eNOS function (1057).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingl-arginine (2.4 g/day for 4 wk) improves endothelial function and decreases homocysteine levels in patients with elevated blood pressure and hyperhomocysteinuria.
“Other recent studies show improved endothelial function and insulin sensitivity in patients with impaired glucose uptake and metabolic syndrome (6.6 g/day l-arginine for 2 wk) (663) and improved endothelial function and decreased homocysteine levels in patients with elevated blood pressure and hyperhomocysteinuria (2.4 g/day for 4 wk) (781).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingWhen ADMA levels are low, effects of exogenous l-arginine are limited; therapy seems more beneficial in patients with higher ADMA levels, in which treatment increases l-arginine/ADMA ratios and improves endothelial function.
“It has been noted that when ADMA levels are low, the effects of exogenous l-arginine are limited; however, the therapy seems to be more beneficial in patients with higher ADMA levels, in which the treatment increases the l-arginine/ADMA ratios and improves endothelial function (103).”
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Interpretationcitation§ 4. Pharmacological interventions in eNOS uncouplingAt high ADMA concentrations, l-arginine supplementation may not overcome eNOS inhibition, indicating the need to determine l-arginine/ADMA ratios to better assess l-arginine availability.
“At high ADMA concentrations, l-arginine supplementation may not overcome eNOS inhibition, indicating the need to determine l-arginine/ADMA ratios to better assess l-arginine availability (102, 106, 954).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingl-arginine (6.6 g/day for 2 wk) improves endothelial function and insulin sensitivity in patients with impaired glucose uptake and metabolic syndrome.
“Other recent studies show improved endothelial function and insulin sensitivity in patients with impaired glucose uptake and metabolic syndrome (6.6 g/day l-arginine for 2 wk) (663) and improved endothelial function and decreased homocysteine levels in patients with elevated blood pressure and hyperhomocysteinuria (2.4 g/day for 4 wk) (781).”
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Premisecitation§ 1. Mechanisms of ROS productionReverse electron transport ROS generation occurs when succinate is present in high concentration and is responsible in vivo for ROS generated after ischemia upon reperfusion.
“This type of ROS generation occurs when succinate, the substrate for complex II, is present in high concentration and is responsible in vivo for the ROS generated after ischemia upon reperfusion (171, 172).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingArginase inhibition with nor-NG-hydroxy-l-arginine showed protection against ischemia-reperfusion injury and improved endothelial function in patients with coronary artery disease and diabetes and in patients with hypercholesterolemia.
“In these cases, arginase inhibition showed protection against ischemia-reperfusion injury (530) and improved endothelial function in patients with coronary artery disease and diabetes (855) and in patients with hypercholesterolemia (529).”
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Premisecitation§ 1. Mechanisms of ROS productionNOX4 has been reported to be localized within the mitochondrion either constitutively or in specific pathological conditions, although controversial.
“Additionally, although controversial, NOX4 has been reported to be localized within the mitochondrion either constitutively or in specific pathological conditions (152, 306, 540).”
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Premisereasoning§ C. MitochondriaMitochondrial superoxide likely does not escape the mitochondrion; MnSOD catalyzes its dismutation to hydrogen peroxide, which can diffuse out.
“Although this superoxide, being a charged molecule, likely does not escape the mitochondrion, manganese superoxide dismutase (MnSOD) located within the mitochondria catalyzes the dismutation of superoxide to hydrogen peroxide, which can freely diffuse out of the organelle to mediate cellular signaling or contribute to oxidative stress.”
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Premisecitation§ 1. Mechanisms of ROS productionMitochondrial enzymes beyond the ETC-pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and monoamine oxygenase A and B-have been reported to generate ROS.
“Pyruvate dehydrogenase (887), α-ketoglutarate dehydrogenase (130, 887, 952), and monoamine oxygenase A and B (290) have all been demonstrated to serve as ROS sources.”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingExacerbated arginase activity can decrease l-arginine levels and cause eNOS uncoupling.
“Exacerbated arginase activity can decrease l-arginine levels and cause eNOS uncoupling (91, 144, 667, 804, 1039).”
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Premisecitation§ 4. Pharmacological interventions in eNOS uncouplingIn some cases, l-citrulline increased NO synthesis, but no changes in blood pressure were observed.
“In some cases, l-citrulline increased NO synthesis, but no changes in blood pressure were observed (506).”
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Interpretationnone given§ 2. Physiological role of mitochondrial ROSMitochondrial ROS both mediate essential vascular signaling pathways and can contribute to the pathogenesis of cardiovascular disease.
“Accumulating data now demonstrate that mitochondrial ROS both mediate essential vascular signaling pathways and can also contribute to the pathogenesis of cardiovascular disease.”
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Premisenone given§ 2. Physiological role of mitochondrial ROSDuring myocardial ischemia, the ETC as well as the NADH and quinone pools become maximally reduced, and there is a significant buildup of succinate, the substrate for complex II.
“During myocardial ischemia, the ETC as well as the NADH and quinone pools become maximally reduced. Additionally, there is a significant buildup of succinate, the substrate for complex II, which further supports the reduction of the quinone pool.”
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Premisereasoning§ 1. Mechanisms of ROS productionComplex I is the most significant site of superoxide generation within the ETC and produces superoxide by two distinct mechanisms depending on the reduction status of the ETC and strength of the proton-motive force.
“Complex I, a 1,000-kDa protein comprised of ~45 subunits, is the most significant site of superoxide generation within the ETC and produces superoxide by two distinct mechanisms depending on the reduction status of the ETC and strength of the proton-motive force across the inner mitochondrial membrane (FIGURE 13).”
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Premisecitation§ 2. Physiological role of mitochondrial ROSTissue from the left ventricle of heart failure patients showed an increase in superoxide production and a decrease in MnSOD protein levels and activity.
“Notably, tissue from the left ventricle of heart failure patients showed an increase in superoxide production and a decrease in MnSOD protein levels and activity, consistent with a role for increased mitochondrial superoxide in the pathogenesis of heart failure (814).”
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Premisenone given§ 1. Mechanisms of ROS productionComplex III also represents a site of superoxide production within the ETC, although the rate is significantly lower than by reverse electron transport through complex I.
“Complex III also represents a site of superoxide production within the ETC, although the rate of generation at this site is significantly lower than by reverse electron transport through complex I.”
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Premisereasoning§ 1. Mechanisms of ROS productionWhen electron supply is high through the ETC, coenzyme Q downstream of complex I becomes reduced, and a high proton-motive force can push electrons in reverse from coenzyme Q to the complex I FMN, generating superoxide by reverse electron transport.
“In contrast, when electron supply is high through the ETC, coenzyme Q downstream of complex I becomes reduced. A high proton-motive force present in this condition can then push electrons in the reverse direction from coenzyme Q to the complex I FMN, generating superoxide by reverse electron transport.”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionThe N-terminal domain of XOR contains the two Fe/S clusters, a central domain contains the FAD cofactor and a NAD+/H binding site, and the C-terminal domain contains the molybdopterin cofactor and a purine binding site.
“The N-terminal domain contains the two Fe/S clusters, a central domain contains the FAD cofactor, and a NAD+/H binding site and the C-terminal domain contains the molybdopterin cofactor and a purine binding site (268).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionSzeto-Schiller peptides mediate protection in animal models of ischemia/reperfusion and insulin resistance.
“These peptides have been shown to mediate protection in animal models of ischemia/reperfusion (922) and insulin resistance (27).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionMitoQ consists of the antioxidant ubiquinol linked to the lipophilic cation triphenylphosphonium.
“This small molecule consists of the antioxidant ubiquinol linked to the lipophilic cation triphenylphosphonium (500).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionOther nitrogen-centered molecules, such as nitrite, promote S-nitrosation of complex I and attenuate ischemia/reperfusion injury.
“Notably, other nitrogen-centered molecules, such as nitrite, have been shown to promote S-nitrosation of complex I and attenuate ischemia/reperfusion injury (864).”
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Premisecitation§ 1. ROS generation by XORThis XDH ROS production only produces significant levels of ROS if NAD+ levels are low, which can happen in vascular hypoxia.
“This reaction only produces significant levels of ROS if NAD+ levels are low; however, these conditions can happen in the setting of vascular hypoxia (406, 562).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionMitoQ has been shown to be protective against ischemia/reperfusion injury, cardiac hypertrophy, and hypertension in animal models.
“MitoQ has been used extensively in animal models of disease and been shown to be protective against ischemia/reperfusion injury, cardiac hypertrophy, and hypertension (210, 211) among other pathologies.”
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Interpretationreasoning§ 2. Physiological role of mitochondrial ROSThis dysfunction occurs not only through direct reaction of superoxide with NO but is also associated with oxidative damage of mitochondrial DNA and proteins.
“This dysfunction occurs not only through the direct reaction of superoxide with NO but is also associated with the oxidative damage of mitochondrial DNA and proteins.”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionIn Parkinson's patients, MitoQ showed no difference in motor function compared with placebo, but the trial established that administration of MitoQ to humans for 1 yr is safe.
“Although Parkinson’s patients taking MitoQ showed no difference in motor function compared with those on placebo treatment, this trial did establish that administration of MitoQ to humans for 1 yr is safe (874).”
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Premisereasoning§ 3. Pharmacological interventions at the level of mitochondrial functionXOR catalyzes the stepwise oxidations of hypoxanthine to xanthine and xanthine to uric acid.
“The enzyme has an important role in the catabolism of purines, catalyzing the stepwise oxidations of hypoxanthine to xanthine and xanthine to uric acid.”
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Premisenone given§ 3. Pharmacological interventions at the level of mitochondrial functionXOR is expressed as XDH but can become XO by posttranslational modifications.
“Xanthine oxidoreductase (XOR) is expressed as a xanthine dehydrogenase (XDH) but can become XO by posttranslational modifications (FIGURE 15).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionSS-31 is a small water-soluble tetrapeptide that accumulates within the mitochondrion and binds to cardiolipin in the inner mitochondrial membrane where it scavenges ROS and prevents lipid peroxidation.
“Szeto–Schiller-31 (SS-31) (Bendavia/elamipretide; Stealth Peptides) is a small water-soluble tetrapeptide that accumulates within the mitochondrion and binds to cardiolipin in the inner mitochondrial membrane where it scavenges ROS and prevents lipid peroxidation (921) (FIGURE 14).”
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Premisecitation§ 2. Physiological role of mitochondrial ROSDecreased MnSOD activity or increased mitochondrial superoxide generation causes endothelial dysfunction and impairs acetylcholine-dependent vasodilation, particularly with age.
“Decreased MnSOD activity or increased mitochondrial superoxide generation causes endothelial dysfunction and impairs acetylcholine-dependent vasodilation, particularly with age (1005).”
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Premisecitation§ 2. Physiological role of mitochondrial ROSMitochondrial ROS have been implicated in pathways leading to cell proliferation and senescence and in activation of JNK and NF-κB.
“Additionally, mitochondrial ROS have been implicated in pathways leading to cell proliferation and senescence (233, 1046) as well as in the activation of other major cell signaling molecules such as the MAP kinase JNK and NF-κB (330, 689).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionXOR is a dimeric protein containing one molybdopterin cofactor, two iron/sulfur clusters, and one FAD per 145-kDa subunit.
“XOR is a dimeric protein containing one molybdopterin cofactor, two iron/sulfur clusters (2Fe/2S), and one molecule of FAD per 145-kDa subunit.”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionS-nitrosation of Cys39 in the ND3 subunit of complex I inhibits its catalytic activity and attenuates reverse electron transport and ROS production.
“This S-nitrosation of Cys39 in the ND3 subunit of complex I inhibits its catalytic activity and, hence, attenuates reverse electron transport and ROS production (170).”
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Premisecitation§ 2. Physiological role of mitochondrial ROSActivation of AMP kinase can lead to mitochondrial biogenesis and increased mitochondrial number, and this pathway can also be stimulated by mitochondrial hydrogen peroxide-dependent activation of Akt.
“Although activation of AMP kinase can lead to mitochondrial biogenesis and increased mitochondrial number, this pathway can also directly be stimulated by mitochondrial hydrogen peroxide-dependent activation of the MAP kinase Akt (911, 919).”
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Premisecitation§ 2. Physiological role of mitochondrial ROSMitochondria have been proposed to serve as a cellular oxygen sensor, such that in hypoxic conditions, mitochondrial ROS production by complex III leads to stabilization of HIF1α and downstream hypoxic adaptation.
“For example, mitochondria have been proposed to serve as a cellular oxygen sensor, such that in hypoxic conditions, mitochondrial ROS production by complex III leads to the stabilization of HIF1α and downstream hypoxic adaptation (84, 997).”
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Premisecitation§ 3. Pharmacological interventions at the level of mitochondrial functionNitrite administered before or during cardiac ischemia protects cardiac function and attenuates infarct size in small and large animal models.
“Nitrite administered before or during cardiac ischemia has been shown to protect cardiac function and attenuate infarct size in a number of small and large animal models (226, 374, 864).”
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Premisecitation§ 2. Physiological role of mitochondrial ROSMitochondrial ROS are required for the differentiation of some hematopoietic stem cells and human mesenchymal stem cells.
“On a cellular level, mitochondrial ROS have also been shown to be required for the differentiation of some hematopoietic stem cells as well as human mesenchymal stem cells (707, 948).”
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Premisecitation§ 1. ROS generation by XORXO activity is increased by angiotensin II, TNF-α, LPS, IL-6, and hypoxia.
“XO is expressed in ECs (393), and its activity is increased by angiotensin II (551), TNF-α, LPS (117, 311), IL-6, and hypoxia (410, 748).”
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Premisenone given§ 2. Pharmacological interventions targeting XOAllopurinol is structurally similar to the XO substrate hypoxanthine and is metabolized to the active compound oxypurinol.
“Allopurinol is structurally similar to the XO substrate hypoxanthine and is metabolized to the active compound oxypurinol (FIGURE 16).”
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Premisecitation§ 2. Pharmacological interventions targeting XOFebuxostat is a XO inhibitor developed by Teijin, with higher selectivity and potency than allopurinol and oxypurinol.
“Febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazole carboxylic acid) (TEI-6720, TMX-67) (FIGURE 16) is a XO inhibitor developed by Teijin, with higher selectivity and potency than allopurinol and oxypurinol (702).”
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Premisecitation§ 1. ROS generation by XORComparison of crystal structures for XDH and XO indicates movement of a loop that partially blocks the NAD+ binding site and alters the electrostatics of the FAD environment.
“The comparison of the crystal structures for XDH and XO indicates the movement of a loop that partially blocks the NAD+ binding site and alters the electrostatics of the FAD environment (268, 542).”
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Premisecitation§ 2. Pharmacological interventions targeting XOFebuxostat was approved in 2008 in Europe and by the FDA in 2009 for the treatment of gout.
“Febuxostat was approved in 2008 in Europe and by the Food and Drug Administration in 2009 for the treatment of gout (commercial name Uloric in United States, Adenuric in Europe) (76, 77, 837).”
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Premisenone given§ 2. Pharmacological interventions targeting XOTopiroxostat is a novel XO inhibitor developed by Fuji Yahuhin Co. Ltd.
“Topiroxostat (FYX-051, 4-[5-pyridin-4-yl-1H-[1, 2, 4] triazol-3-yl]pyridine-2-carbonitrile) (FIGURE 16) is a novel XO inhibitor developed by Fuji Yahuhin Co. Ltd.”
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Premisecitation§ 1. ROS generation by XORXO catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid, generating hydrogen peroxide and superoxide in a reaction amplified under ischemia and hypoxia.
“Thus, XO catalyzes the oxidation of hypoxanthine to xanthine and subsequently xanthine to uric acid, generating hydrogen peroxide and superoxide in a reaction amplified under ischemia and hypoxia (147, 307, 496, 497, 499).”
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Premisereasoning§ 1. ROS generation by XORXO shows decreased affinity for NAD+ and increased O2 affinity.
“XO shows a decreased affinity for NAD+ and increased O2 affinity.”
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Premisecitation§ 2. Pharmacological interventions targeting XOFebuxostat's selectivity is partly due to a lack of structural resemblance with purines, which also reduces side effects of purine and pyrimidine metabolism.
“The selectivity is partly due to a lack of structural resemblance with purines; this also reduces side effects of purine and pyrimidine metabolism (1041).”
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Interpretationreasoning§ 2. Pharmacological interventions targeting XOThe higher affinity and specificity of febuxostat can have advantages over allopurinol and oxypurinol.
“The higher affinity and specificity of febuxostat can have advantages over allopurinol and oxypurinol.”
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Premisecitation§ 2. Pharmacological interventions targeting XOBoth allopurinol and oxypurinol have been used for the treatment of gout for decades.
“Both allopurinol and oxypurinol have been used for the treatment of gout for decades (305, 710).”
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Premisenone given§ 1. Peroxidases and COXMammalian peroxidases are activated by reaction with hydrogen peroxide to generate an oxidizing heme species that can hydroxylate or oxygenate a substrate.
“These proteins are activated by their reaction with hydrogen peroxide to generate an oxidizing heme species that can hydroxylate or oxygenate a substrate.”
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Premisecitation§ 1. Peroxidases and COXMPO, lactoperoxidase, and eosinophil peroxidase are integral components of the immune defense.
“MPO, lactoperoxidase, and eosinophil peroxidase are integral components of the immune defense (516).”
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Premisecitation§ 1. Peroxidases and COXSome interplay between COX-2 and other ROS/RNS-generating proteins such as iNOS and XO has been described.
“Interestingly, some interplay between COX-2 and other ROS/RNS-generating proteins such as iNOS (52) and XO (701) have been described.”
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Premisecitation§ 1. Peroxidases and COXMPO is found predominantly in neutrophils and monocytes and catalyzes the reaction of hydrogen peroxide to produce several reactive species, mainly hypochlorous acid (HOCl).
“MPO is found predominantly in neutrophils and monocytes and catalyzes the reaction of hydrogen peroxide to produce several reactive species, mainly hypochlorous acid (HOCl) (discussed in sect. IVB) (516, 1021).”
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Premisecitation§ 2. Pharmacological interventions targeting XONitrite has been used to inhibit XO-catalyzed ROS generation and to take advantage of its nitrite reductase activity to generate NO while decreasing superoxide production.
“Nitrite has also been used to inhibit XO-catalyzed ROS generation and to take advantage of its nitrite reductase activity to generate NO (reviewed in sect. IIB3) while decreasing superoxide production (1071).”
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Premisecitation§ 2. LipoxygenasesLipoxygenases catalyze the insertion of oxygen in polyunsaturated fatty acids.
“Lipoxygenases catalyze the insertion of oxygen in polyunsaturated fatty acids (119, 535, 1040) and are also biological sources of superoxide (537).”
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Premisenone given§ 1. Peroxidases and COXMammalian peroxidases include thyroid peroxidase, myeloperoxidase (MPO), lactoperoxidase, eosinophil peroxidase, and COX.
“Mammalian peroxidases include thyroid peroxidase, myeloperoxidase (MPO), lactoperoxidase, eosinophil peroxidase, and COX.”
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Premisecitation§ 1. Peroxidases and COXCOX are proteins from the peroxidase family, evolutionarily related to the peroxidase enzymes of the immune system.
“COX are proteins from the peroxidase family, evolutionarily related to the peroxidase enzymes of the immune system (1052).”
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Premisecitation§ 2. LipoxygenasesSeveral lipoxygenases have been related to inflammation and cardiovascular disease, in particular 5-lipoxygenase and 12/15-lipoxygenase.
“Several lipoxygenases have been related to inflammation and cardiovascular disease, in particular, 5-lipoxygenase and 12/15-lipoxygenase (203, 597, 636).”
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Premisecitation§ 2. Pharmacological interventions targeting XOOther proteins related to direct or indirect production of ROS in the cardiovascular system include peroxidases, cyclooxygenases (COX), lipoxygenases, monoamine oxidase, heme oxygenase (HO), glucose oxidase, cytochrome b5 reductase, and CYPOR.
“Other proteins have been related to the direct or indirect production of ROS in the cardiovascular system, including, but not limited to, peroxidases, cyclooxygenases (COX), lipoxygenases, monoamine oxidase, heme oxygenase (HO), glucose oxidase, cytochrome b5 reductase, and CYPOR (209, 505, 790, 908).”
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Premisecitation§ 2. Pharmacological interventions targeting XOTopiroxostat is a potent inhibitor of XO and induces a covalent modification in the enzyme that inactivates XO after complex dissociation.
“Topiroxostat is a potent inhibitor of XO and induces a covalent modification in the enzyme that inactivates XO after complex dissociation (629, 703, 821).”
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Premisenone given§ 1. Peroxidases and COXMammalian peroxidases are heme proteins that catalyze the oxidation of a wide range of substrates.
“Mammalian peroxidases are heme proteins that catalyze the oxidation of a wide range of substrates.”
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Premisecitation§ 1. Peroxidases and COXCOX produce a variety of prostaglandins, lipid oxidation products with important physiological effects.
“They utilize lipid substrates, generally arachidonic acid, and produce a variety of prostaglandins, lipid oxidation products with important physiological effects (156).”
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Premisecitation§ 1. Peroxidases and COXCOX utilize lipid substrates, generally arachidonic acid.
“They utilize lipid substrates, generally arachidonic acid, and produce a variety of prostaglandins, lipid oxidation products with important physiological effects (156).”
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Premisecitation§ 3. AOAO appears to play an important role in drug metabolism and other metabolic pathways.
“Although the function of AO in mammals is yet to be established (434, 935), AO appears to play an important role in drug metabolism and other metabolic pathways (335, 512, 513, 756, 920).”
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Premisecitation§ IV. OTHER ROSOxidation of cysteine residues on metalloproteinases by peroxynitrite results in the activation of these enzymes, which may be detrimental to tissue integrity and repair.
“In contrast, oxidation of cysteine residues on metalloproteinases results in the activation of these enzymes, which may also be detrimental to tissue integrity and repair (992).”
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Premisecitation§ 5. HOHO catalyzes the degradation of protoporphyrin IX (heme b) to biliverdin.
“This enzyme catalyzes the degradation of the protoporphyrin IX (heme b) to biliverdin (805, 806).”
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Premisecitation§ IV. OTHER ROSThe reaction of NO with superoxide to form peroxynitrite occurs at a diffusion-limited rate and is governed by the flux of NO and superoxide production.
“This reaction occurs at a diffusion-limited rate and is governed by the flux of NO and superoxide production (78).”
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Premisecitation§ IV. OTHER ROSTyrosine nitration is measured as the hallmark of peroxynitrite presence and is traditionally viewed as a sign of nitrative or oxidative stress.
“This modification is measured as the hallmark of peroxynitrite presence and is traditionally viewed as a sign of nitrative or oxidative stress (78, 765).”
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Premisecitation§ 5. HOHigh levels of HO-1 are present in the spleen, consistent with an important role in the processing of heme from red blood cell turnover.
“High levels of HO-1 are present in the spleen, consistent with an important role in the processing of heme from red blood cell turnover (713, 805).”
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Premisecitation§ 5. HOHO mediates the degradation of heme in mammals.
“HO mediates the degradation of heme in mammals. This enzyme catalyzes the degradation of the protoporphyrin IX (heme b) to biliverdin (805, 806).”
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Premisecitation§ IV. OTHER ROSOxidation of tyrosine phosphatases by peroxynitrite results in the inhibition of their enzymatic activity and the aberrant propagation of phosphorylative signaling.
“Oxidation of tyrosine phosphatases results in the inhibition of their enzymatic activity and the aberrant propagation of phosphorylative signaling (926).”
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Premisecitation§ IV. OTHER ROSPeroxynitrite can abstract a hydrogen atom to initiate lipid peroxidation, a detrimental process that can lead to cytotoxicity.
“For example, lipids are also a significant biological target for peroxynitrite, and although the species can abstract a hydrogen atom to initiate lipid peroxidation, a detrimental process that can lead to cytotoxicity in many cases (65, 766), peroxynitrite can also mediate lipid nitration (54, 1027).”
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Premisecitation§ IV. OTHER ROSThrough these signaling mechanisms, nitrated lipids mediate a number of physiological effects in animal models including attenuation of inflammatory bowel disease, protection after ischemia/reperfusion, decreases in atherosclerosis, and reversal of obesity-induced pulmonary hypertension.
“Through these signaling mechanisms, nitrated lipids mediate a number of physiological effects in animal models including attenuation of inflammatory bowel disease (113), protection after ischemia/reperfusion (683, 801), decreases in atherosclerosis (800), and reversal of obesity-induced pulmonary hypertension (495).”
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Premisecitation§ IV. OTHER ROSIn proteins, HOCl predominantly oxidizes cysteine and methionine residues to disulfide and methionine sulfoxide, respectively.
“Although HOCl reacts with a variety of biomolecule targets (755), in proteins, it predominantly oxidizes cysteine and methionine residues to disulfide and methionine sulfoxide, respectively (726).”
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Premisecitation§ C. Hydroxyl RadicalIn the cardiovascular system, increased free iron and/or copper can be related to aging or hemolytic disease.
“In the cardiovascular system, this can be related to aging (122) or hemolytic disease (1026).”
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Interpretationreasoning§ IV. OTHER ROSNitration of proteins decreases enzyme activity, disrupts metabolism and cellular detoxification, perturbs cytoskeletal organization, and ultimately contributes to the cytotoxic effects of peroxynitrite.
“Importantly, the nitration of these proteins decreases enzyme activity, disrupts metabolism and cellular detoxification, perturbs cytoskeletal organization, and ultimately contributes to the cytotoxic effects of peroxynitrite.”
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Premisecitation§ C. Hydroxyl RadicalOH· is generally formed as a product of Fenton reactions involving free iron or copper ions and hydrogen peroxide or from the reaction of hydrogen peroxide with superoxide (Haber-Weiss reaction).
“In this context, OH· is generally formed as a product of Fenton reactions involving free iron or copper ions (Fe2+; Cu+) and hydrogen peroxide (Eq. 26) (281, 986) or from the reaction of hydrogen peroxide with superoxide (Haber–Weiss reaction) (Eq. 27) (394).”
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Premisecitation§ C. Hydroxyl RadicalThe source of this iron is most likely plasma-released Hb; the reaction of plasma Hb with peroxides can cause the release of free iron.
“The source of this iron is most likely plasma-released Hb; whereas Hb or heme are not catalysts for the Fenton reaction, the reaction of plasma Hb with peroxides can cause the release of free iron (389, 759).”
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Premisecitation§ IV. OTHER ROSPrimary mechanisms of nitrated fatty acid signaling include activation of PPARγ and Michael addition to thiol-containing proteins in a number of signaling pathways.
“Primary mechanisms of nitrated fatty acid signaling include activation of PPARγ (55, 583) and Michael addition to thiol-containing proteins in a number of signaling pathways (53, 955).”
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Premisecitation§ IV. OTHER ROSHypochlorous acid (HOCl) is generated by the enzyme MPO, localized within leukocytes.
“Hypochlorous acid (HOCl) is generated by the enzyme MPO, localized within leukocytes by the following reaction (300) (Eq. 25)”
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Premisecitation§ IV. OTHER ROSHOCl reacts more slowly with tyrosine residues to mediate the formation of 3-chlorotyrosine.
“Additionally, HOCl reacts more slowly with tyrosine residues to mediate the formation of 3-chlorotyrosine (1019).”
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Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCESIn nitroglycerin tolerance, the development of tolerance was mainly due to mitochondrial ROS release and was independent of NOX, whereas activation of NOX triggered by mitochondrial ROS was the effector of endothelial dysfunction associated with nitroglycerin tolerance.
“In this case, the development of tolerance was mainly due to mitochondrial ROS release and was independent of NOX, whereas the activation of NOX, triggered by mitochondrial ROS, was the effector of the endothelial dysfunction associated to nitroglycerin tolerance (1004).”
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Premisecitation§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESThe situation of antioxidant use has been termed the "antioxidant paradox".
“In fact, the situation has been termed the “antioxidant paradox” (399, 400).”
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Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCESIn response to increased levels of ROS, PKC is activated, which in turn can activate NOXs.
“In response to the increased levels of ROS, the PKC is activated, which in turn, can activate NOXs (319, 776).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCESActivation of NOX via angiotensin II and the angiotensin II type 1 receptor is mediated by PKC; PKCε is also an activator of the KATP channel, which stimulates mitochondrial ROS production.
“Of note, the activation of NOX via angiotensin II and the angiotensin II type 1 receptor is mediated by PKC; however, the isoform PKCε is also an activator of the KATP channel, which, as indicated, also stimulates mitochondrial ROS production (FIGURE 17) (187, 242).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ 3. Carbonate radicalSeveral examples of biological oxidations mediated by the bicarbonate anion, in particular through interactions with peroxynitrite, have been reported.
“Several examples of biological oxidations mediated by the bicarbonate anion, in particular through interactions with peroxynitrite, have been reported in the literature [e.g., (46, 635, 918, 1056)].”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ 2. Dinitrogen trioxideDinitrogen trioxide (N2O3) is a strong nitrosating species also formed in the oxidation of NO.
“Dinitrogen trioxide (N2O3) is a strong nitrosating species also formed in the oxidation of NO (Eq. 29) (691, 692, 1018).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ 3. Carbonate radicalXO has been characterized as a target and source of carbonate radical.
“In relation to cardiovascular biology, it is important to note that XO has also been characterized as a target and source of carbonate radical (111).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [111] source
Not checked in the free run.
May combine two claims.
Premisecitation§ 3. Carbonate radicalThe carbonate radical can be formed in vivo by the reaction of the hydroxyl radical with carbonate or bicarbonate or via the reaction of peroxynitrite with carbon dioxide.
“The carbonate radical can be formed in vivo by the reaction of the hydroxyl radical with carbonate or bicarbonate (138) or via the reaction of peroxynitrite with carbon dioxide (Eq. 30) (112, 608, 640).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ C. Hydroxyl RadicalThe binding of NO to heme iron can limit heme reactivity and prevent iron release from heme.
“The binding of NO to heme iron can also limit heme reactivity and prevent iron release from heme (482).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [482] source
Not checked in the free run.
May combine two claims.
Premisecitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCESXO is indirectly activated by angiotensin II, increasing cellular ROS production.
“Secondary to the main role of mitochondria and NOX, but not to be ignored, XO and eNOS can also amplify the formation of ROS; for instance, XO is indirectly activated by angiotensin II, increasing cellular ROS production (551).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [551] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Interpretationcitation§ V. CROSS-TALK BETWEEN ROS AND RNS SOURCESThe existence of many different routes interconnecting ROS/RNS sources may suggest that normalization of dysfunctional conditions is a herculean task; however, it also presents the promise of normalizing a disease state by the direct inhibition of a single source of oxidative stress.
“The existence of many different routes interconnecting ROS/RNS sources may suggest that the normalization of dysfunctional conditions is a herculean task; however, it also presents the promise of normalizing a disease state by the direct inhibition of a single source of oxidative stress.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ 1. Nitrogen dioxideNitrogen dioxide (NO2·) is formed in the reaction of NO with oxygen.
“Nitrogen dioxide (NO2·) is formed in the reaction of NO with oxygen (Eq. 28) (509, 1018).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESNO, through its high affinity for heme groups or via S-nitrosation, can act as an important modulator of NOX or can modulate the insertion of heme in the receptor sGC.
“In another example, NO, through its high affinity for heme groups or via S-nitrosation, can act as an important modulator of NOX (176, 315, 846) or can also modulate the insertion of heme in the receptor sGC.”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
Interpretationnone given§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESAdvances on NOX research have led to the development of novel inhibitors on their way to widespread use for the treatment of cardiovascular disease and other pathologies.
“Advances on NOX research have led to the development of novel inhibitors on their way to widespread use for the treatment of cardiovascular disease and other pathologies.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Interpretationnone given§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESThe ability to interact with different oxidation states of sGC and use pharmacological tools to recover sGC-dependent signaling provides a new tool for the treatment of conditions in which NO signaling is compromised.
“The ability to interact with different oxidation states of sGC and use pharmacological tools to recover sGC-dependent signaling provides a new tool for the treatment of conditions in which NO signaling is compromised.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESIt is clearer now that specific inhibitors directed to the sources of ROS can yield more effective therapies.
“It is clearer now that specific inhibitors directed to the sources of ROS can yield more effective therapies.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationnone given§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESWe have progressed from a simpler approach leveraging antioxidant vitamins and ROS scavengers, which failed, to a more fundamental discovery of the enzymatic sources and reaction pathways of ROS.
“In summary, we have progressed from a simpler approach leveraging antioxidant vitamins and ROS scavengers, which failed, to a more fundamental discovery of the enzymatic sources and reaction pathways of ROS.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Interpretationreasoning§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESNew highly specific inhibitors of other ROS sources like the XO-targeted febuxostat and mitochondrial-targeted drugs provide additional pathways to modulate cellular ROS production.
“New highly specific inhibitors of other ROS sources like the XO-targeted febuxostat and mitochondrial-targeted drugs provide additional pathways to modulate cellular ROS production.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESA better understanding of NOS function has allowed the development of new strategies to couple eNOS and target downstream effectors like sGC.
“A better understanding of NOS function has allowed the development of new strategies to couple eNOS and target downstream effectors like sGC.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationcitation§ VI. CONCLUDING REMARKS: ADVANCES, CHALLENGES, AND THERAPEUTIC OPPORTUNITIESAntioxidants targeted to specific cells or organelles can still become relevant in the management of oxidative stress pathologies, in particular mitochondria-targeted antioxidants.
“Finally, antioxidants targeted to specific cells or organelles can still become relevant in the management of oxidative stress pathologies, in particular, but not limited to, mitochondria-targeted antioxidants (873).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [873] source
Not checked in the free run.
The paper relies on this without support.
The distribution of R-state and T-state Hb in vivo is regulated by oxygen concentration.
“As the distribution of R-state and T-state Hb in vivo are regulated by oxygen concentration, this phenomenon has important relevance for the reaction in vivo.”
The paper relies on this without support.
In the cardiovascular system, the heart is the most relevant organ for the function of Mb as a nitrite reductase.
“In the cardiovascular system, the heart is the most relevant organ for the function of Mb as a nitrite reductase.”
The paper relies on this without support.
NADPH oxidases (NOXs) are the most important sources of superoxide and hydrogen peroxide generation in the vasculature quantitatively.
“Among these, NADPH oxidases (NOXs) appear to be the most important sources quantitatively.”
The paper relies on this without support.
Hydrogen peroxide does not scavenge NO.
“As hydrogen peroxide does not scavenge NO, changes in NOX4 activity do not directly impact NO levels.”
The paper relies on this without support.
Superoxide formation from monomeric eNOS is low compared with the uncoupled dimer.
“The superoxide formation from the monomer is low as compared with the uncoupled dimer, and thus, this mechanism does not increase the rate of superoxide formation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Nitric oxide •NO is formed extensively by enzymatic and non-enzymatic processes and serves as an intra- and intercellular signalling molecule.
“Another radical formed extensively by both enzymatic and non-enzymatic processes is nitric oxide •NO, which serves as an intra- and intercellular signalling molecule [115,116].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [116]
Interplay between the endothelium and established exerkines such as nitric oxide and VEGF influences vascular tone, inflammation, regeneration and thrombosis, and has an important role in cardiovascular and overall resilience.
“interplay between the endothelium and established exerkines, such as nitric oxide52 and VEGF27, has been shown to influence vascular tone, inflammation, regeneration and thrombosis, and has an important role in cardiovascular and overall resilience67.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [52]
The interplay between the endothelium and the exerkines NO• and VEGF can modulate vascular tone, inflammation, regeneration, and thrombosis, with an important role in cardiovascular resilience.
“Notably, the interplay between the endothelium and the exerkines NO• 174 and VEGF 175 can modulate vascular tone, inflammation, regeneration, and thrombosis, with an important role in cardiovascular resilience-that is, absence of actual CVD despite existing risk factors.176”
From Exercise benefits in cardiovascular diseases: From mechanisms to clinical implementation (2023) · cites this paper as [174]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Ataciguat is called a stimulator in the activators section
MinorThe paper distinguishes sGC stimulators from activators, but calls ataciguat a stimulator while placing it in the section on activators.
“Another sGC stimulator that has reached clinical use is HMR 1766 (ataciguat) (827) (FIGURE 6).”
“B) activators. sGC activators are compounds that can trigger the catalytic activity of sGC independently of the redox state of the sGC heme or even in the absence of bound heme.”
NOX1 deletion is described as having no effect despite cited enhanced atherosclerosis
MinorThe text says study 875 found no effect of NOX1 deletion, but the cited study's title says NOX1 deficiency was associated with enhanced atherosclerosis.
“whereas in other cases, NOX1 deletion did not seem to have an effect (875).”
“NOX1 deficiency in apolipoprotein E-knockout mice is associated with elevated plasma lipids and enhanced atherosclerosis.”
Molybdopterin is said both not to react with oxygen and to be oxidized by it
MinorOne passage says the molybdopterin group does not react directly with oxygen; another attributes oxidation of its Mo4+ center to molecular oxygen.
“As the molybdopterin group does not react directly with oxygen or NO, these reactions that decrease NO release from heme proteins do not limit Mo-dependent nitrite reduction reactions.”
“This is most probably related to the fast oxidation of the Mo4+ species to Mo6+ by molecular oxygen as observed in other molybdopterin proteins (880, 990).”
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- Authors
- Tejero, J., Shiva, S., & Gladwin, M. T.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2019-01-01
- Volume
- 99
- Issue
- 1
- Pages
- 311-379
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- PMC
- PMC6442925
- OpenAlex
- W2898816123
- Semantic Scholar
- 694ff5d6eb081e8d0595d1aa47663f94edc7a4de
- Cited by
- 541
- References
- 1,088
- Citations by year
- 2026: 53 · 2025: 65 · 2024: 82 · 2023: 105 · 2022: 94 · 2021: 62 · 2020: 57 · 2019: 23
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Physiological Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (R01 HL098032, R01 HL125886, T32 HL110849, T32 HL007563, P01 HL103455)
- HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) (R21 ES027390)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- nitric oxide, reactive oxygen species, vascular signaling, nitric oxide synthase, nitrite reduction, hypoxia, superoxide, hydrogen peroxide, hemoglobin, oxidative enzymes, redox homeostasis, vascular tone, blood flow, cardiovascular disease, therapeutic target
- MeSH terms
- Animals, Cardiovascular Diseases, Cardiovascular System, Humans, Nitric Oxide, Signal Transduction, Reactive Oxygen Species, Oxidative Stress
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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