Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension
Ulf Landmesser, … , William E. Mitch, David G. Harrison
Ulf Landmesser, … , William E. Mitch, David G. Harrison
Published April 15, 2003
Citation Information: J Clin Invest. 2003;111(8):1201-1209. https://doi.org/10.1172/JCI14172.
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Article Vascular biology

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.

Authors

Ulf Landmesser, Sergey Dikalov, S. Russ Price, Louise McCann, Tohru Fukai, Steven M. Holland, William E. Mitch, David G. Harrison

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Figure 1

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Role of the endothelial NO synthase as a source of ROSs in hypertensive ...
Role of the endothelial NO synthase as a source of ROSs in hypertensive vessels. (a) Effect of endothelial removal and NO synthase inhibition (L-NAME, 1 mM) on vascular superoxide (O2•–) production estimated by lucigenin chemiluminescence in sham-operated and DOCA-salt–hypertensive rats (n = 6–10 per group). (b) Vascular O2•– production estimated by lucigenin chemiluminescence in sham-operated and DOCA-salt–hypertensive wild-type (C57BL/6), eNOS–/–, and nNOS–/– knockout mice (n = 6–10 per group). (c) Vascular O2•– production measured by the SOD-inhibitable cytochrome c reduction assay in sham-operated and DOCA-salt–hypertensive wild-type, eNOS–/–, and nNOS–/– knockout mice (n = 5–13 per group).