Cited by 1,957Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionEicosanoids and Hypertension Pharmacology

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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace

Förstermann, Ulrich, Münzel, Thomas·2006·Circulation

DOI 10.1161/circulationaha.105.602532

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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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10.1161/res.86.3.347 · DOI
Li H Witte K August M Brausch I Gödtel-Armbrust U Habermeier A Closs EI Oelze M Münzel T Förstermann U. Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol. In press.
10.1161/res.88.2.e14 · DOI
10.1161/circ.99.15.2027 · DOI
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10.1161/circ.94.11.2756 · DOI
10.1161/circ.101.11.1261 · DOI
10.1161/circ.100.21.2131 · DOI
10.1161/hyp.30.1.57 · DOI
10.1161/res.77.3.510 · DOI
10.1161/circ.103.9.1282 · DOI
10.1161/hyp.33.6.1353 · DOI
10.1161/res.86.1.e7 · DOI
10.1161/res.86.2.e36 · DOI
10.1161/circ.104.10.1119 · DOI
10.1161/res.87.2.99 · DOI
10.1161/res.87.7.566 · DOI
10.1161/hyp.38.5.1044 · DOI
10.1161/circ.104.22.2673 · DOI
10.1161/circ.94.1.6 · DOI
10.1161/circ.97.3.237 · DOI
10.1161/atvb.22.1.6 · DOI
10.1161/atvb.20.1.185 · DOI

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Chrysin attenuates high-fat-diet-induced myocardial oxidative stress via upregulating eNOS and Nrf2 target genes in rats
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“ET-1, a potent endogenous vasoconstrictor [27] and reported pro-inflammatory peptide in the lungs [28], has a direct role in the development of ALI and also worsens its severity by increasing pulmonary microvasculature pressure in early sepsis [29,30].”
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Loss of fatty acid binding protein 3 ameliorates lipopolysaccharide-induced inflammation and endothelial dysfunction
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l ‐Arginine prevents metabolic effects of high glucose in diabetic mice
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Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke
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Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation
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“In endothelial cells, peroxynitrite induces the S-nitrosylation of eNOS and the oxidation of the essential cofactor for NOS, (6R-)5,6,7,8-tetrabiopterin (BH4), resulting in impaired endothelial function through NOS uncoupling.(8) In addition, peroxynitrite also reduces intracellular Larginine concentration by decreasi…”
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Jatrorrhizine Improves Endothelial Function in Diabetes and Obesity through Suppression of Endoplasmic Reticulum Stress
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Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway
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Low dose dietary nitrate improves endothelial dysfunction and plaque stability in the ApoE−/− mouse fed a high fat diet
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Matrix Metalloproteinase-9 Is a Predictive Factor for Systematic Hypertension and Heart Dysfunction in Patients with Obstructive Sleep Apnea Syndrome
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Chronic exposure to tramadol induces cardiac inflammation and endothelial dysfunction in mice
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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
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-04-04
Volume: 113
Issue: 13
Pages: 1708-1714
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.105.602532
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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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace

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