ArticleThe Journal of clinical investigation2003
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 620 papers, 1 of them a synthesis that pooled it.
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Who cites it
620 citing papers in PubMed, 1 synthesis or guideline pooled it, 1,457 citations in OpenAlex.
- Bioactive Compounds and Their Effect on Blood Pressure-A Review.Nutrients · 2020Pooled it
- Effects of Oxygen on Perioperative Vascular Function: A Randomized Clinical Trial.Journal of the American Heart Association · 2025Trial
- The impact of propranolol on nitric oxide and total antioxidant capacity in patients with resistant hypertension-evidence from the APPROPRIATE trial.BMC research notes · 2020Trial
- Gas signaling molecule: a new research focus in the treatment of erectile dysfunction.Medical gas research · 2027Review
- FTO/m6A Regulate Prenatal Nicotine-Induced eNOS Uncoupling and BP Susceptibility.Hypertension (Dallas, Tex. : 1979) · 2026Article
- Endothelial nitric oxide signaling in cellular and systemic metabolism.Redox biology · 2026Review
- Beyond the guidelines: Vascular function as the central determinant and therapeutic target in hypertension.Hypertension research : official journal of the Japanese Society of Hypertension · 2026Review
- DASH Diet, Dietary Nitrate, and Nitric Oxide Bioavailability: Implications for Endothelial Dysfunction and Hypertension in Older Adults.Molecular nutrition & food research · 2026Review
- Molecular damage associated with ageing drives inflammation in cardiovascular disease.Nature reviews. Cardiology · 2026Review
- Nicotine-Mediated Redox and Nitrosative Stress in Cardiorenal Health.Hypertension (Dallas, Tex. : 1979) · 2026Review
- Redox Network Failure in Chronic Kidney Disease: Hydrogen Sulfide Deficiency, Reactive Sulfur Species Dysregulation and the Uremic Toxin-AhR-Mitochondrial Axis.Antioxidants (Basel, Switzerland) · 2026Review
- EndMT in vascular cognitive impairment and dementia: mechanisms, evidence gaps, and therapeutic opportunities.Molecular medicine (Cambridge, Mass.) · 2026Review
- Extracellular Vesicles as Mediators of Endothelial and Tubular Injury in Cardiac Surgery-Associated Acute Kidney Injury.Biomedicines · 2026Review
- Genistein Restores Nitric Oxide Bioavailability and Attenuates Oxidative Stress in Angiotensin II-Induced Hypertensive Mice.Preventive nutrition and food science · 2026Article
- The gut microbiota-aromatic amino acid axis in cardiovascular disease: pathophysiological roles, translational biomarkers, and therapeutic targeting.Frontiers in cardiovascular medicine · 2026Review
- Lipoprotein(a) and Vascular Redox State in Patients With Advanced Coronary Atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- SARS-CoV-2 spike S1-mediated HIF-2α activation in retinal endothelial cells suggests a mechanism contributing to post-COVID endothelial dysfunction.Frontiers in immunology · 2026Article
- Serum Alpha-1-Antitrypsin and Folic Acid as Biomarkers for Glaucoma Risk.Clinical ophthalmology (Auckland, N.Z.) · 2026Article
- Ozone protects against ischemia-reperfusion injury: molecular mechanisms.Frontiers in pharmacology · 2026Review
- NOX2 inhibition attenuates oxidative stress and eNOS uncoupling in pulmonary arteries of rats following simulated air diving.PloS one · 2026Article
560 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become "uncoupled," producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate-salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47(phox) and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.
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Registered trials
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