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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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“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]
In the citing paper
“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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“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 319
eNOS Uncoupling in Cardiovascular Diseases - the Role of Oxidative Stress and Inflammation
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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 322
“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:
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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
“, 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 300
“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
“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 296
Cardiovascular effects and molecular targets of resveratrol
Li, H., Xia, N., & Förstermann, U. (2012) · Nitric Oxide · doi:10.1016/j.niox.2011.12.006 · Cited by 305
Kruk, J., Aboul-Enein, H. Y., Kładna, A., & Bowser, J. E. (2019) · Free Radical Research · doi:10.1080/10715762.2019.1612059 · Cited by 304
Daiber, A., Lisa, F. D., Oelze, M. W., Kröller‐Schön, S., Steven, S., Schulz, E., & Münzel, T. F. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13403 · Cited by 274
Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth
Hu, B., Wang, Q., Wang, Y., Hua, S., Sauvé, C.-E. G., Ong, D. S. T., Lan, Z. D., Chang, Q., Ho, Y. W., Monasterio, M. M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.10.039 · Cited by 277
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“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 262
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
Mikhed, Y., Daiber, A., & Steven, S. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160715918 · Cited by 257
“Uncoupling of eNOS switches the enzyme from good to evil [77].”
BackgroundDuan, H., Zhang, Q., Liu, J., Li, R., Wang, D., Peng, W., & Wu, C. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105599 · Cited by 261
Schulz, E., Wenzel, P., Münzel, T. F., & Daiber, A. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4609 · Cited by 258
“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 265
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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
“Although eNOS normally produces the vasoprotectant molecule, NO, in the absence of either L-arginine or BH4, eNOS can produce O2 .”
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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 249
“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
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Endothelial Damage in Acute Respiratory Distress Syndrome
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Hyperglycemia in Acute Ischemic Stroke: A Vascular Perspective
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“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
Tetrahydrobiopterin in Cardiovascular Health and Disease
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“Elevated ADMA may inhibit NO synthesis by eNOS or even result in eNOS uncoupling, which would further enhance oxidative stress (75).”
Reversal 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 237
ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet
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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
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“commonly associated with cardiometabolic diseases [6].”
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Metadata
- 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 (medical) › 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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