Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease.
NO produced by eNOS (endothelial nitric oxide synthase) is a key mediator of vascular homoeostasis. NO bioavailability is reduced early in vascular disease states, such as hypercholesterolaemia, diabetes and hypertension, and throughout the progression of atherosclerosis. This is a result of both reduced NO synthesis and increased NO consumption by reactive oxygen species. eNOS enzymatic activity appears to be determined by the availability of its cofactor BH4 (tetrahydrobiopterin). When BH4 levels are adequate, eNOS produces NO; when BH4 levels are limiting, eNOS becomes enzymatically uncoupled and generates superoxide, contributing to vascular oxidative stress and endothelial dysfunction. BH4 bioavailability is determined by a balance of enzymatic de novo synthesis and recycling, versus oxidative degradation in dysfunctional endothelium. Augmenting vascular BH4 levels by pharmacological supplementation, by enhancing the rate of de novo biosynthesis or by measures to reduce BH4 oxidation have been shown in experimental studies to enhance NO bioavailability. Thus BH4 represents a potential therapeutic target for preserving eNOS function in vascular disease.
Schmidt
Tim S
TS
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Alp
Nicholas J
NJ
D000818:Animals; D001205:Ascorbic Acid / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014815:Vitamins / Q000627:therapeutic use
D017382:Reactive Oxygen Species; D014815:Vitamins; D001708:Biopterins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D001205:Ascorbic Acid