Cellular targets and mechanisms of nitros(yl)ation: An insight into their nature and kinetics in vivo
Open accessAbstract
There is mounting evidence that the established paradigm of nitric oxide (NO) biochemistry, from formation through NO synthases, over interaction with soluble guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part of a richer chemistry through which NO elicits biological signaling. Additional pathways have been suggested that include interaction of NO-derived metabolites with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls. Despite the overwhelming attention paid in this regard to RSNOs, little is known about the stability of these species, their significance outside the circulation, and whether other nitros(yl)ation products are of equal importance. We here show that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S-nitrosation in vivo and that the products of these reactions are constitutively present throughout the organ system. Our study further reveals that all NO-derived products are highly dynamic, have fairly short lifetimes, and are linked to tissue oxygenation and redox state. Experimental evidence further suggests that nitroso formation occurs substantially by means of oxidative nitrosylation rather than NO autoxidation, explaining why S-nitrosation can compete effectively with nitrosylation. Moreover, tissue nitrite can serve as a significant extravascular pool of NO during brief periods of hypoxia, and tissue nitrate/nitrite ratios can serve as indicators of the balance between local oxidative and nitrosative stress. These findings vastly expand our understanding of the fate of NO in vivo and provide a framework for further exploration of the significance of nitrosative events in redox sensing and signaling. The findings also raise the intriguing possibility that N-nitrosation is directly involved in the modulation of protein function.
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Tissue levels of S-nitrosothiols are enhanced through nitrite reduction due to NOS inhibition, hypoxia, and acidosis, suggesting that tissue nitrite stores can be regarded as a backup and on-demand NO donor.
“Indeed, the tissue levels of S-nitrosothiols (NO-mediated signaling molecules) are enhanced through the nitrite reduction due to NOS inhibition, hypoxia, and acidosis [97], suggesting that the tissue nitrite stores can be regarded as a backup and on-demand NO donor.”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [97]
The nitrite level in cardiac tissue is a couple of times higher than in plasma due to an unknown form of active transport from blood to tissues or due to oxidation of endogenously generated NO to nitrite by ceruloplasmin, and serves as a significant extravascular pool for NO during tissue hypoxia.
“The nitrite level in cardiac tissue is a couple of times higher than that in plasma due to an unknown form of active transport from blood to tissues or due to the oxidation of endogenously generated-NO to nitrite by ceruloplasmin [96], and serves as a significant extravascular pool for NO during tissue hypoxia [97].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [97]
The speed with which nitrite affects the total vascular sulfide pool suggests a direct interaction rather than an effect of nitrite on H2S production.
“The speed with which nitrite affects the total vascular sulfide pool suggests a direct interaction rather than an effect of nitrite on H2S production as systemic NOS inhibition is not known to lead to comparable drops in nitrite that quickly [78].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [78]
Sulfide concentrations in rodents are higher in tissues than in blood, and the highest concentrations are observed in the vasculature, rendering the aorta a relevant target for the interaction of nitrite with sulfide.
“As with nitrite [78], sulfide concentrations in rodents are higher in tissues than in blood, and the highest concentrations are observed in the vasculature [79], rendering the aorta a relevant target for the interaction of nitrite with sulfide.”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [78]
Intraperitoneal administration of nitrite in rats results in a rapid redistribution of this anion to all organs within 5 minutes or less.
“intraperitoneal administration of nitrite in rats results in a rapid (≤ 5min) redistribution of this anion to all organs [50, 96].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [96]
Nitrite supplementation to intact organisms is associated with a widespread increase in the concentration of nitrite and production of NO-derived species such as S-nitrosothiols or nitrosylhemes in several tissues.
“Many reports show that nitrite supplementation to intact organisms is associated with a widespread increase in the concentration of this anion and production of NO-derived species such as S-nitrosothiols or nitrosylhemes in several tissues[25, 43, 46, 48, 49, 96].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [96]
A potential mechanism by which nitrite could induce cGMP-independent effects is S-nitrosation of cysteine residues, a potential nitrite-induced post-translational modification that can alter protein function.
“A potential mechanism by which nitrite could induce cGMP-independent effects is S-nitrosation of cysteine residues, which is being increasingly recognized as a potential nitrite-induced post-translational modification that can alter protein function[17, 43, 46, 47, 51, 96].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [96]
NO bioactivity in blood and tissue is preserved in the form of nitrite, nitrate, S-nitrosothiols, N-nitrosamines, nitrosylhemoglobin, and S-nitrosohemoglobin.
“However studies conducted in this area over the last few years have unraveled mechanisms by which NO bioactivity in blood and in tissue have been preserved in the form of nitrite, nitrate, S-nitrosothiols (RSNO), N-nitrosamines (RNNO), nitrosylhemoglobin (NOHb), and S-nitrosohemoglobin (SNOHb) [16–21].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [20]
NO is readily oxidized to nitrite and subsequently nitrate in an oxygen dependent manner; physiological concentrations of nitrite vary between tissues reflecting the degree of NOS activity as well as oxidation pathways of NO.
“NO is readily oxidized to nitrite and subsequently nitrate in an oxygen dependent manner; thus, the physiological concentrations of nitrite vary between tissues reflecting the degree of NOS activity as well as oxidation pathways of NO [20, 45].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [20]
Nitrite is more concentrated within cells and tissues (low μM) compared to plasma.
“Conversely, nitrite is more concentrated within cells and tissues (low μM) compared to plasma [20, 46, 47].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [20]
Nitrite anion itself can stimulate cGC activity and other signaling mediators, as treatment with NO scavenger carboxy-PTIO was unable to prevent these effects.
“work from Bryan et al demonstrated that nitrite anion itself could stimulate cGC activity and other signaling mediators as treatment with the NO scavenger carboxy-PTIO was unable to prevent these effects by nitrite administration [20].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [20]
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Self-citationSodium nitrite: The “cure” for nitric oxide insufficiency
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Acute neurotoxic effects of the fungal metabolite ochratoxin-A
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Nitric oxide synthase reduces nitrite to NO under anoxia
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Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis
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Self-citationDietary Nitrate, Nitric Oxide, and Cardiovascular Health
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Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure
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Self-citationReactions of Synthetic [2Fe-2S] and [4Fe-4S] Clusters with Nitric Oxide and Nitrosothiols
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Inorganic nitrite and nitrate: evidence to support consideration as dietary nutrients
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Self-citationNitric Oxide Availability as a Marker of Oxidative Stress
Pierini, D., & Bryan, N. S. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1441-8_5 · Cited by 128 · see citing works
Self-citationS -Nitrosation versus S -Glutathionylation of Protein Sulfhydryl Groups by S -Nitrosoglutathione
Giustarini, D., Milzani, A., Aldini, G., Carini, M., Rossi, R., & Dalle‐Donne, I. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.930 · Cited by 131 · see citing works
The Key Role of Nitric Oxide in Hypoxia: Hypoxic Vasodilation and Energy Supply–Demand Matching
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Nitric oxide synthase-derived plasma nitrite predicts exercise capacity
Rassaf, T., Lauer, T., Heiss, C., Balzer, J., Mangold, S., Leyendecker, T., Rottler, J., Drexhage, C., Meyer, C., & Kelm, M. (2007) · British Journal of Sports Medicine · doi:10.1136/bjsm.2007.035758 · Cited by 122 · see citing works
Self-citationNitrite Reduction and Cardiovascular Protection
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Nitric oxide and its derivatives in the cancer battlefield
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On the chemical biology of the nitrite/sulfide interaction
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Self-citationPlasma Nitroso Compounds Are Decreased in Patients With Endothelial Dysfunction
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Self-citationInorganic nitrite therapy: historical perspective and future directions
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Discriminating formation of HNO from other reactive nitrogen oxide species
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Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers
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The nitric oxide pathway and possible therapeutic options in pre‐eclampsia
Johal, T., Lees, C., Everett, T. R., & Wilkinson, I. B. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12301 · Cited by 108 · see citing works
A comparison of organic and inorganic nitrates/nitrites
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RBC NOS: regulatory mechanisms and therapeutic aspects
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NO-Rich Diet for Lifestyle-Related Diseases
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Self-citationGenetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
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Self-citationMitochondria as metabolizers and targets of nitrite
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Nitrite reduction by molybdoenzymes: a new class of nitric oxide-forming nitrite reductases
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Nitric-Oxide Supplementation for Treatment of Long-Term Complications in Argininosuccinic Aciduria
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Self-citationMyocardial protection by nitrite
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Effects of nitrite on modulating ROS generation following ischemia and reperfusion
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- Authors
- Bryan, N. S., Rassaf, T., Maloney, R. E., Rodriguez, C. M., Saijo, F., Rodriguez, J. R., & Feelisch, M.
- Affiliations
- Boston University (US)
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130; and Whitaker Cardiovascular Institute, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-03-10
- Volume
- 101
- Issue
- 12
- Pages
- 4308-4313
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC384737
- OpenAlex
- W2039979152
- Cited by
- 400
- References
- 33
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 10 · 2016: 15 · 2015: 20 · 2014: 23 · 2013: 17 · 2012: 23
- FWCI
- 22.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01 HL69029, R01HL069029)
- 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 › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- nitrosation, nitric oxide, S-nitrosylation, N-nitrosation, S-nitrosothiols, nitrite, nitrate, tissue oxygenation, redox state, hypoxia, nitric oxide signaling, protein function modulation, in vivo kinetics
- MeSH terms
- Animals, Hypoxia, Heme, Kinetics, Male, Nitric Oxide, Nitrosamines, Oxidation-Reduction, Signal Transduction, Nitrosation, Rats, Sprague-Dawley, Rats, Wistar, Nitric Oxide Synthase, Rats
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