Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension

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 p47phox 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

Endothelial nitric oxide synthase dysfunction in diabetic mice: importance of tetrahydrobiopterin in eNOS dimerisation

“…BH4 bioavailability is postulated to be limiting in diabetic vascular disease [29]. Loss of BH4 can uncouple eNOS synthesis [17].…”

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

“…These include vascular homologues of the leukocyte NADPH oxidase [38], cytochrome P450 [60], the mitochondrial electron transport chain [61], and uncoupled NO synthase [62]. Ox-PAPC may impair endothelial cell function by uncoupling endothelial nitric oxide synthase activity in a manner analogous to the effects of LDL.…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…[30][31][32] This review will focus on ROS, the vascular system and hypertension, specifically relating to the clinical significance. All vascular cell types produce ROS, including endothelial, smooth muscle, adventitial fibroblasts and perivascular adipocytes, and can be formed by many enzymes, including xanthine oxidoreductase, uncoupled nitric oxide synthase, mitochondrial respiratory enzymes and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [37][38][39][40][41][42][43][44] (Figure 1). Of these mitochondrial enzymes and NADPH oxidase seem to be particularly important in hypertension.…”