Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace
Abstract
Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate l -arginine to l -citrulline and NO·. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate l -arginine, and the essential cofactor (6 R )-5,6,7,8-tetrahydro- l -biopterin (BH 4 ), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O 2 · − ) reacts avidly with vascular NO· to form peroxynitrite (ONOO − ). The cofactor BH 4 is highly sensitive to oxidation by ONOO − . Diminished levels of BH 4 promote O 2 · − production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH 4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH 4 levels as well.
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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).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [303]
Vascular disease, cardiovascular disease, and metabolic syndrome all share effective loss of NO function.
“Similarly, vascular disease, cardiovascular disease (CVD), and metabolic syndrome all share effective loss of NO function[23,35–39].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [23]
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“Peroxynitrite, the direct reaction product of NO and superoxide, is capable of oxidizing BH4 and thus leading to BH 4 deficiency [5, 64].”
BackgroundOxidative Stress in Preeclampsia and Placental Diseases
Aouache, R., Biquard, L., Vaiman, D., & Miralles, F. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051496 · Cited by 645 · see citing works
“In the absence of BH4, eNOS shifts from a homodimeric to a monomeric form, thus becoming uncoupled [14].”
BackgroundImpact of Oxidative Stress on the Heart and Vasculature
Münzel, T. F., Camici, G. G., Maack, C., Bonetti, N. R., Fuster, V., & Kovacic, J. C. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.035 · Cited by 623 · see citing works
“Nitric oxide is a key antiatherogenic component, which inhibits platelet adhesion and aggregation, powerfully augments vasodilation through stimulation of cGMP production by SMCs, decreases leukocyte-endothelial interactions, and reduces SMC proliferation (25).”
Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576 · see citing works
Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies
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“Vascular NO induces vasodilation, inhibits platelet aggregation and adhesion, prevents oxidative modification of LDL cholesterol, limits vascular smooth-muscle-cell proliferation by specific actions on the cell cycle, and decreases the expression of proinflammatory genes that promote the development of atherosclerosis”
BackgroundAntioxidant effects of resveratrol in the cardiovascular system
Xia, N., Daiber, A., Förstermann, U., & Li, H. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13492 · Cited by 576 · see citing works
Oxidative stress and vascular inflammation in aging
Assar, M. E., Angulo, J., & Rodríguez‐Mañas, L. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.003 · Cited by 576 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Environmental Noise and the Cardiovascular System
Münzel, T. F., Schmidt, F. P., Steven, S., Herzog, J., Daiber, A., & Sørensen, M. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.12.015 · Cited by 539 · see citing works
“Reactive oxygen species scavenge nitric oxide and cause endothelial nitric oxide synthase (eNOS) uncoupling through oxidation of the eNOS cofactor tetrahydrobiopterin and eNOS S-glutathionylation, thereby further increasing vascular oxidative stress (71).”
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New developments and novel therapeutic perspectives for vitamin C
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“The effects of oxidative stress on the cardiovascular system are multifold and include: 1) ROS-induced apoptosis of endothelial cells (62,63); 2) induction of inflammation by oxidative modification of the expression of proinflammatory genes (64) and cell adhesion (65); 3) reduction of intracellular bioavailability of…”
BackgroundTargeting vascular (endothelial) dysfunction
Daiber, A., Steven, S., Weber, A., Shuvaev, V. V., Muzykantov, V. R., Laher, I., Li, H., Lamas, S., & Münzel, T. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13517 · Cited by 501 · see citing works
“…nitration and inactivation of prostacyclin synthase (CYP8A1), oxidative activation of the endothelin-1 system and direct inactivation of •NO by superoxide play important roles in the development of endothelial dysfunction (for review see Forstermann and Munzel, 2006; Daiber et al., 2014, 2017).”
BackgroundOxidative stress and endothelial dysfunction in hypertension
Schulz, E., Gori, T., & Münzel, T. F. (2011) · Hypertension Research · doi:10.1038/hr.2011.39 · Cited by 503 · see citing works
Inflammatory Response Mechanisms of the Dentine–Pulp Complex and the Periapical Tissues
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“In inflammation, NADPH oxidases are strongly active in the vascular wall and generate higher concentrations of O2 [70,115].”
BackgroundMechanisms of Disease: oxidative stress and inflammation in the pathogenesis of hypertension
Vaziri, N. D., & Rodríguez-Iturbe, B. (2006) · Nature Clinical Practice Nephrology · doi:10.1038/ncpneph0283 · Cited by 442 · see citing works
Nutrition, physical activity, and cardiovascular disease: An update
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“1 elucidates the cascade of oxidation-327 sensitive events and NO generation [45] in relation to some antioxidant intervention.”
BackgroundMechanisms of lead-induced hypertension and cardiovascular disease
Vaziri, N. D. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00158.2008 · Cited by 441 · see citing works
“Oxidative stress can limit NO availability by several mechanisms, including avid inactivation/sequestration of NO by ROS, depletion of the NOS cofactor tetrahydrobiopterin, and uncoupling of eNOS (23).”
Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety
Shaito, A. A., Thuan, D. T. B., Hoa, P. T., Nguyen, T. H. D., Hasan, H. A., Halabi, S., Abdelhady, S., Nasrallah, G. K., Eid, A. H., & Pintus, G. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00422 · Cited by 439 · see citing works
Cardiovascular Effects of Exercise Training
Gielen, S., Schuler, G. C., & Adams, V. (2010) · Circulation · doi:10.1161/circulationaha.110.939959 · Cited by 434 · see citing works
Endothelial dysfunction : the early predictor of atherosclerosis
Mudau, M., Genis, A., Lochner, A., & Strijdom, H. (2012) · Cardiovascular Journal of Africa · doi:10.5830/cvja-2011-068 · Cited by 521 · see citing works
“According to the literature, cardiovascular risk factors are associated with upregulation of ROS sources, especially NADPH oxidase.(7,20) However, other sources of ROS such as xanthine oxidase, cyclooxygenase (COX) and mitochondria also play a role.”
BackgroundInfluentialNitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension
Schulz, E., Jansen, T., Wenzel, P., Daiber, A., & Münzel, T. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1989 · Cited by 430 · see citing works
“Very in-triguing are observations that the eNOS itself can be a superoxide source, thereby causing endothelial dysfunction (14).”
Oxidative Stress-Induced Endothelial Dysfunction in Cardiovascular Diseases
Shaito, A. A., Aramouni, K., Assaf, R., Parenti, A., Orekhov, A. N., EL‐Yazbi, A. F., Pintus, G., & Eid, A. H. (2022) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2703105 · Cited by 427 · see citing works
Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation
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“eNOS uncoupling was shown in a variety of experimental and clinical vascular disease states, especially in diabetes (6,7,33,35).”
BackgroundInfluentialDietary Phosphorus Acutely Impairs Endothelial Function
Shuto, E., Taketani, Y., Tanaka, R., Harada, N., Isshiki, M., Sato, M., Nashiki, K., Amo, K., Yamamoto, H., Higashi, Y., et al. (2009) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008101106 · Cited by 400 · see citing works
Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction
Münzel, T. F., Sinning, C., Post, F., Warnholtz, A., & Schulz, E. (2008) · Annals of Medicine · doi:10.1080/07853890701854702 · Cited by 399 · see citing works
“The mechanism underlying eNOS uncoupling have recently been discussed in detail (for review see (66))”
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Münzel, T., Gori, T., Keaney, J. F., Maack, C., & Daiber, A. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv305 · Cited by 394 · see citing works
RONS and Oxidative Stress: An Overview of Basic Concepts
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“NO • is an essential molecule of cellular signaling that functions protectively in vascular endothelium, as eNOS is the most critical enzyme for NO • production [63].”
Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis
Mani, S., Li, H., Untereiner, A., Wu, L., Yang, G., Austin, R. C., Dickhout, J. G., Lhoták, Š., Meng, Q. H., & Wang, R. (2013) · Circulation · doi:10.1161/circulationaha.113.002208 · Cited by 377 · see citing works
“Increased oxidative stress also contributes to the development of atherosclerosis.(36) GSH is cytoprotective against oxidative damage by neutralizing lipid peroxidase and Figure 5.”
BackgroundThe Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling
Pacurari, M., Kafoury, R., Tchounwou, P. B., & Ndebele, K. (2014) · International Journal of Inflammation · doi:10.1155/2014/689360 · Cited by 377 · see citing works
“Mechanistically, aliskiren and valsartan combination downregulates NADPH oxidase activity and therefore attenuates oxidative stress [59], which plays a key role in initiating the development of vascular inflammation and cardiovascular disease.”
InfluentialeNOS uncoupling and endothelial dysfunction in aged vessels
Yang, Y., Huang, A., Kaley, G., & Sun, D. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00230.2009 · Cited by 370 · see citing works
“This alteration is referred to as “eNOS uncoupling” and is linked to an increased monomerization of the enzyme (15, 32).”
BackgroundEndothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice
Zhao, H. J., Wang, S., Cheng, H., Zhang, M., Takahashi, T., Fogo, A. B., Breyer, M. D., & Harris, R. C. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070798 · Cited by 359 · see citing works
“There is growing evidence that endothelial cell dysfunction contributes to hypertension and microvascular complications of diabetes (2,23).”
BackgroundHomocysteine-Induced Endothelial Dysfunction
Lai, W. K. C., & Kan, M. Y. (2015) · Annals of Nutrition and Metabolism · doi:10.1159/000437098 · Cited by 360 · see citing works
Janaszak-Jasiecka, A., Płoska, A., Wierońska, J. M., Dobrucki, L. W., & Kalinowski, L. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00423-2 · Cited by 358 · see citing works
A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis
Jansson, E. Å., Huang, L., Malkey, R., Govoni, M., Nihlén, C., Olsson, A., Stensdotter, M., Petersson, J., Holm, L., Weitzberg, E., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.92 · Cited by 356 · see citing works
“92" language="eng" relation="no"> NO generated from L -arginine ( 1 ) and molecular oxygen by NO synthases has a key role in regulation of cardiovascular homeostasis, and a reduced NO bioavailability is a central event in several major disorders including hypertension, atherosclerosis and ischemic heart diseas”
BackgroundWentzel, J. J., Chatzizisis, Y. S., Gijsen, F. J. H., Giannoglou, G. D., Feldman, C. L., & Stone, P. H. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs217 · Cited by 355 · see citing works
Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction
Xu, J., & Zou, M. (2009) · Circulation · doi:10.1161/circulationaha.108.835223 · Cited by 348 · see citing works
Cardiovascular Adaptations to Exercise Training
Hellsten, Y., & Nyberg, M. (2015) · Comprehensive physiology · doi:10.1002/cphy.c140080 · Cited by 415 · see citing works
Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation
Joffre, J., & Hellman, J. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0027 · Cited by 356 · see citing works
“This phenomenon is named NOS uncoupling, as superoxide generation mainly occurs when NOS is not coupled with its cofactor or substrate (52, 103).”
Schmidt, F. P., Basner, M., Kroger, G., Weck, S., Schnorbus, B., Muttray, A., Sariyar, M., Binder, H., Gori, T., Warnholtz, A., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht269 · Cited by 340 · see citing works
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Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches
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“Usually, most cardiovascular risk factors are associated with the up-regulation of intracellular oxidative stress and reactive oxygen species (ROS), which promotes several mechanisms, such as the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NO inactivation, formation of peroxynitrite (ONO…”
BackgroundPathophysiology of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Review
Dodd, W., Laurent, D., Dumont, A. S., Hasan, D. M., Jabbour, P. M., Starke, R. M., Hosaka, K., Polifka, A. J., Hoh, B. L., & Chalouhi, N. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.121.021845 · Cited by 316 · see citing works
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“sidered to be a major contributor to the pathogenesis of vascular diseases, such as hypertension and atherosclerosis.(2,3)”
Melatonin: An Established Antioxidant Worthy of Use in Clinical Trials
Korkmaz, A., Reiter, R. J., Topal, T., Manchester, L. C., Öter, Ş., & Tan, D. (2009) · Molecular Medicine · doi:10.2119/molmed.2008.00117 · Cited by 319 · see citing works
“During this process, several adhesion molecules and monocyte chemoattractant proteins also become involved, widening the inflammatory response and vascular events (17,24).”
BackgroundRole of reactive oxygen and nitrogen species in the vascular responses to inflammation
Kvietys, P. R., & Granger, D. N. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.002 · Cited by 313 · see citing works
eNOS Uncoupling in Cardiovascular Diseases - the Role of Oxidative Stress and Inflammation
Karbach, S., Wenzel, P., Waisman, A., Munzel, T., & Daiber, A. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113196660748 · Cited by 307 · see citing works
Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets
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“The affected intestinal endothelium generally shows a diminished amount of eNOS versus its normal counterpart (72).”
Daiber, A., Xia, N., Steven, S., Oelze, M. W., Hanf, A., Kröller‐Schön, S., Münzel, T. F., & Li, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20010187 · Cited by 312 · see citing works
“eNOS uncoupling is characterized by leakage of electrons from the transport chain in the reductase domain (from NADPH over flavins FMN and FAD) and transfer to molecular oxygen yielding superoxide instead of NO, thereby switching the enzyme from a nitric oxide to a superoxide source [21,22].”
BackgroundNon-Invasive Vascular Function Tests:
Tomiyama, H., & Yamashina, A. (2009) · Circulation Journal · doi:10.1253/circj.cj-09-0534 · Cited by 298 · see citing works
Judkins, C. P., Diep, H., Broughton, B. R. S., Mast, A. E., Hooker, E. U., Miller, A. A., Selemidis, S., Dusting, G. J., Sobey, C. G., & Drummond, G. R. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00799.2009 · Cited by 299 · see citing works
“, oxygen reduction is uncoupled from L-arginine oxidation such that it switches from an antiatherogenic NO-producing enzyme to one that generates superoxide, thereby itself becoming a contributor to vascular oxidative stress (13).”
BackgroundDiabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury
Fakhruddin, S., Alanazi, W. A., & Jackson, K. E. (2017) · Journal of Diabetes Research · doi:10.1155/2017/8379327 · Cited by 295 · see citing works
“Peroxynitrite is a potent oxidant which not only damages cellular proteins, lipids, and nucleic acid but also oxidizes BH4 resulting in its depletion which in turn leads to NOS uncoupling and dysfunction.”
BackgroundInfluentialOxidative stress and metabolic pathologies: from an adipocentric point of view
Le Lay, S., Simard, G., Martinez, M. C., & Andriantsitohaina, R. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/908539 · Cited by 291 · see citing works
“The transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been well described in endothelial cells and observed in different models of cardiovascular diseases, including patients with cardiovascular risk factors [27].”
BackgroundROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications
Moldogazieva, N. T., Mokhosoev, I. M., Feldman, N. B., & Lutsenko, S. V. (2018) · Free Radical Research · doi:10.1080/10715762.2018.1457217 · Cited by 291 · see citing works
Cardiovascular effects and molecular targets of resveratrol
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Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth
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Carlström, M., Persson, A. E. G., Larsson, E., Hezel, M., Scheffer, P. G., Teerlink, T., Weitzberg, E., & Lundberg, J. O. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq366 · Cited by 261 · see citing works
“Nitric oxide (NO) is a key regulator of cardiovascular homeostasis with reduced NO bioavailability being a central underlying pathological event in many cardiovascular disorders including hypertension and atherosclerosis.(7,8) An increase in renal and vascular oxidative stress is thought to be involved in salt-induced…”
BackgroundMarchesi, C., Ebrahimian, T., Angulo, O. J., Paradis, P., & Schiffrin, E. L. (2009) · Hypertension · doi:10.1161/hypertensionaha.109.138305 · Cited by 261 · see citing works
Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials
Antoniades, C. A., Antonopoulos, A. S., Tousoulis, D., Marinou, K., & Stefanadis, C. (2008) · European Heart Journal · doi:10.1093/eurheartj/ehn515 · Cited by 258 · see citing works
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“This switch is even more detrimental than inhibition of eNOS since uncoupling will switch the enzyme from an NO to a superoxide source, meaning from a protective/beneficial to a harmful/toxic phenotype (45, 95).”
Definitions and pathophysiology of vasoplegic shock
Lambden, S., Creagh-Brown, B. C., Hunt, J. E. A., Summers, C., & Forni, L. G. (2018) · Critical Care · doi:10.1186/s13054-018-2102-1 · Cited by 254 · see citing works
Horke, S., Witte, I., Wilgenbus, P., Krüger, M., Strand, D. J., & Förstermann, U. (2007) · Circulation · doi:10.1161/circulationaha.106.681700 · Cited by 245 · see citing works
Kim, J. H., Bugaj, L. J., Oh, Y. J., Bivalacqua, T. J., Ryoo, S., Soucy, K. G., Santhanam, L., Webb, A. K., Camara, A., Sikka, G., et al. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91393.2008 · Cited by 244 · see citing works
“Although eNOS normally produces the vasoprotectant molecule, NO, in the absence of either L-arginine or BH4, eNOS can produce O2 .”
BackgroundInfluentialSchuler, G. C., Adams, V., & Goto, Y. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht111 · Cited by 244 · see citing works
Redox Signaling, Vascular Function, and Hypertension
Lee, M. Y., & Griendling, K. K. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1986 · Cited by 241 · see citing works
“Although eNOS uncoupling is attributed to diverse mechanisms in experimental conditions, a decrease in BH 4 bioavailability is the most important mechanism in physiological or pathological conditions (49).”
Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function
Viswambharan, H., Carvas, J. M., Antic, V., Marecic, A., Jud, C., Zaugg, C. E., Ming, X., Montani, J., Albrecht, U., & Yang, Z. (2007) · Circulation · doi:10.1161/circulationaha.106.653303 · Cited by 242 · see citing works
Endothelial Damage in Acute Respiratory Distress Syndrome
Vassiliou, A. G., Kotanidou, Α., Dimopoulou, I., & Orfanos, S. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228793 · Cited by 239 · see citing works
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Hyperglycemia in Acute Ischemic Stroke: A Vascular Perspective
Martini, S. R., & Kent, T. A. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600355 · Cited by 238 · see citing works
“Loss of NO bioavailability has been found under a number of pathological conditions, including hyperglycemia (Forstermann and Munzel, 2006).”
BackgroundInfluentialEndothelial Arginase II: A Novel Target for the Treatment of Atherosclerosis
Ryoo, S., Gupta, G., Benjo, A., Lim, H. K., Camara, A., Sikka, G., Lim, H. K., Sohi, J., Santhanam, L., Soucy, K., et al. (2008) · Circulation Research · doi:10.1161/circresaha.107.169573 · Cited by 236 · see citing works
Tetrahydrobiopterin in Cardiovascular Health and Disease
Bendall, J. K., Douglas, G., McNeill, E., Channon, K. M., & Crabtree, M. J. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5566 · Cited by 231 · see citing works
“Elevated ADMA may inhibit NO synthesis by eNOS or even result in eNOS uncoupling, which would further enhance oxidative stress (75).”
Mikhed, Y., Daiber, A., & Steven, S. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160715918 · Cited by 257 · see citing works
“Uncoupling of eNOS switches the enzyme from good to evil [77].”
BackgroundReversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin
Moens, A. L., Takimoto, E., Tocchetti, C. G., Chakir, K., Bedja, D., Cormaci, G., Ketner, E., Majmudar, M. D., Gabrielson, K., Halushka, M. K., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.737031 · Cited by 235 · see citing works
ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet
Terasaka, N., Yu, S., Yvan‐Charvet, L., Wang, N., Mzhavia, N., Langlois, R., Pagler, T. A., Li, R., Welch, C. L., Goldberg, I. J., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35470 · Cited by 232 · see citing works
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“data is supportive of the pharmacology of the aforementioned resveratrol stent [105], and novel dosage forms from the activation of eNOS and upstream effectors relating to cardiovascular disease [88,106].”
Backgroundl-Citrulline Supplementation: Impact on Cardiometabolic Health
Allerton, T. D., Proctor, D. N., Stephens, J. M., Dugas, T. R., Spielmann, G., & Irving, B. A. (2018) · Nutrients · doi:10.3390/nu10070921 · Cited by 235 · see citing works
“commonly associated with cardiometabolic diseases [6].”
BackgroundErdogdu, Ö., Nathanson, D., Sjöholm, Å., Nyström, T., & Zhang, Q. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.04.022 · Cited by 229 · see citing works
- Authors
- Förstermann, U., & Münzel, T.
- Affiliations
- From the Departments of Pharmacology (U.F.) and Internal Medicine II (Cardiology) (T.M.), Johannes Gutenberg University Hospitals, Mainz, Germany.
- Venue
- Circulation
- Published
- 2006-04-04
- Volume
- 113
- Issue
- 13
- Pages
- 1708-1714
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2146190354
- Cited by
- 1,957
- References
- 67
- Citations by year
- 2026: 93 · 2025: 76 · 2024: 99 · 2023: 86 · 2022: 110 · 2021: 113 · 2020: 110 · 2019: 89 · 2018: 105 · 2017: 105 · 2016: 117 · 2015: 101 · 2014: 123 · 2013: 98 · 2012: 85
- FWCI
- 62.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- endothelial nitric oxide synthase, nitric oxide, tetrahydrobiopterin, eNOS uncoupling, NADPH oxidase, reactive oxygen species, superoxide, peroxynitrite, oxidative stress, cardiovascular risk factors, hypertension, hypercholesterolemia, diabetes mellitus, smoking, folic acid, vitamin C, L-arginine
- MeSH terms
- Animals, Endothelium, Vascular, Humans, Nitric Oxide, Vascular Diseases, Reactive Oxygen Species, Oxidative Stress, Nitric Oxide Synthase Type III
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