Gene transfer of human guanosine 5'-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-09, Vol.108 (10), p.1238-1245
• Main Authors: ZHENG, Jie-Sheng, YANG, Xiang-Qun, LOOKINGLAND, Keith J, FINK, Gregory D, HESSLINGER, Christian, KAPATOS, Gregory, KOVESDI, Imre, CHEN, Alex F
• Format: Article
• Language: English
• Subjects: Acetophenones - therapeutic use; Animals; Antioxidants - therapeutic use; Arterial hypertension. Arterial hypotension; Atrasentan; Biological and medical sciences; Biopterins - analogs & derivatives; Biopterins - deficiency; Biopterins - metabolism; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Arteries - drug effects; Carotid Arteries - physiopathology; Cyclic N-Oxides - therapeutic use; Desoxycorticosterone; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1 - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Experimental diseases; Gene Transfer Techniques; Genetic Therapy - methods; GTP Cyclohydrolase - genetics; GTP Cyclohydrolase - metabolism; GTP Cyclohydrolase - pharmacology; Humans; Hypertension - chemically induced; Hypertension - physiopathology; Hypertension - therapy; In Vitro Techniques; Male; Medical sciences; Nitric Oxide - metabolism; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium Chloride; Spin Labels; Superoxides - metabolism; Vasodilation - drug effects
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000089082.40285.C3

We recently reported that arterial superoxide (O2-) is augmented by increased endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt hypertension, a model of low renin hypertension. Tetrahydrobiopterin (BH4), a potent reducing molecule with antioxidant properties and an essential cofactor for endothelial nitric oxide synthase, protects against O2--induced vascular dysfunction. However, the interaction between O2- and BH4 on endothelial function and the underlying mechanisms are unknown. The present study tested the hypothesis that BH4 deficiency due to ET-1-induced O2- 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 BH4 biosynthesis, reverses such deficiency and endothelial dysfunction in carotid arteries of DOCA-salt rats. There were significantly increased arterial O2- levels and decreased GTPCH I activity and BH4 levels in DOCA-salt compared with sham rats. Treatment of arteries of DOCA-salt rats with the selective ETA receptor antagonist ABT-627, NADPH oxidase inhibitor apocynin, or superoxide dismutase (SOD) mimetic tempol abolished O2- and restored BH4 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 BH4 levels, resulting in reduced O2- and improved endothelium-dependent relaxation and basal NO release in DOCA-salt rats. These results indicate that a BH4 deficiency resulting from ET-1-induced O2- via an ETA/NADPH oxidase pathway leads to endothelial dysfunction, and gene transfer of GTPCH I reverses the BH4 deficiency and endothelial dysfunction by reducing O2- in low renin mineralocorticoid hypertension.