Endothelium-specific GTP cyclohydrolase I overexpression attenuates blood pressure progression in salt-sensitive low-renin hypertension.

Journal article

BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor of endothelial nitric oxide synthase (eNOS). When BH4 levels are decreased, eNOS becomes uncoupled to produce superoxide anion (O2(-)) instead of NO, which contributes to endothelial dysfunction. Deoxycorticosterone acetate (DOCA)-salt hypertension is characterized by a suppressed plasma renin level due to sodium retention but manifests in eNOS uncoupling; however, how endogenous BH4 regulates blood pressure is unknown. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for de novo BH4 synthesis. This study tested the hypothesis that endothelium-specific GTPCH I overexpression retards the progression of hypertension through preservation of the structure and function of resistance mesenteric arteries. METHODS AND RESULTS: During 3 weeks of DOCA-salt treatment, arterial blood pressure was increased significantly in wild-type mice, as determined by radiotelemetry, but this increase was attenuated in transgenic mice with endothelium-specific GTPCH I overexpression (Tg-GCH). Arterial GTPCH I activity and BH4 levels were decreased significantly in wild-type DOCA-salt mice, but both were preserved in Tg-GCH mice despite DOCA-salt treatment. Significant remodeling of resistance mesenteric arteries (approximately 100-microm outside diameter) in wild-type DOCA-salt mice exists, evidenced by increased medial cross-sectional area, media thickness, and media-lumen ratio and overexpression of tenascin C, an extracellular matrix glycoprotein that contributes to hypertrophic remodeling; all of these effects were prevented in DOCA-salt-treated Tg-GCH mice. Furthermore, NO-mediated relaxation in mesenteric arteries was significantly improved in DOCA-salt-treated Tg-GCH mice, in parallel with reduced O2(-) levels. Finally, phosphorylation of eNOS at serine residue 1177 (eNOS-S1177), but not its dimer-monomer ratio, was decreased significantly in wild-type DOCA-salt mice compared with sham controls but was preserved in DOCA-salt-treated Tg-GCH mice. CONCLUSIONS: These results demonstrate that endothelium-specific GTPCH I overexpression abrogates O2(-) production and preserves eNOS phosphorylation, which results in preserved structural and functional integrity of resistance mesenteric arteries and lowered blood pressure in low-renin hypertension.

Authors: Du, Y; Guan, Y; Alp, N; Channon, K; Chen, A

• Publication status: Published
• Journal: Circulation
• Volume: 117
• Issue: 8
• Pages: 1045-1054
• Publication date: 2008-02-01
• DOI: 10.1161/circulationaha.107.748236
• EISSN: 1524-4539
• ISSN: 0009-7322
• Language: English
• Keywords: Body Weight; Endothelium, Vascular; Biopterin; Reactive Oxygen Species; Mice, Inbred C57BL; Male; Mice, Transgenic; GTP Cyclohydrolase; Tenascin; Gene Expression Regulation, Enzymologic; Mineralocorticoids; Renin; Vasodilation; Sodium Chloride; Vascular Resistance; Nitric Oxide Synthase Type III; Animals; Nitric Oxide; Desoxycorticosterone; Coronary Vessels; Hypertension; Blood Pressure; Mice; Nitric Oxide Synthase Type II; Mesenteric Arteries