Gene Transfer of Human Guanosine 5′-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension

Abstract

Background— We recently reported that arterial superoxide (O 2 − ) is augmented by increased endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt hypertension, a model of low renin hypertension. Tetrahydrobiopterin (BH 4 ), a potent reducing molecule with antioxidant properties and an essential cofactor for endothelial nitric oxide synthase, protects against O 2 − –induced vascular dysfunction. However, the interaction between O 2 − and BH 4 on endothelial function and the underlying mechanisms are unknown. Methods and Results— The present study tested the hypothesis that BH 4 deficiency due to ET-1–induced O 2 − leads to impaired endothelium-dependent relaxation and that gene transfer of human guanosine 5′-triphosphate (GTP) cyclohydrolase I (GTPCH I), the first and rate-limiting enzyme for BH 4 biosynthesis, reverses such deficiency and endothelial dysfunction in carotid arteries of DOCA-salt rats. There were significantly increased arterial O 2 − levels and decreased GTPCH I activity and BH 4 levels in DOCA-salt compared with sham rats. Treatment of arteries of DOCA-salt rats with the selective ET A receptor antagonist ABT-627, NADPH oxidase inhibitor apocynin, or superoxide dismutase (SOD) mimetic tempol abolished O 2 − and restored BH 4 levels. Basal arterial NO release and endothelium-dependent relaxations were impaired in DOCA-salt rats, conditions that were improved by apocynin or tempol treatment. Gene transfer of GTPCH I restored arterial GTPCH I activity and BH 4 levels, resulting in reduced O 2 − and improved endothelium-dependent relaxation and basal NO release in DOCA-salt rats. Conclusions— These results indicate that a BH 4 deficiency resulting from ET-1–induced O 2 − via an ET A /NADPH oxidase pathway leads to endothelial dysfunction, and gene transfer of GTPCH I reverses the BH 4 deficiency and endothelial dysfunction by reducing O 2 − in low renin mineralocorticoid hypertension.