Published Online
on February 11, 2008

A more recent version of this article appeared on February 26, 2008

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Submitted on March 6, 2007
Accepted on December 14, 2007

Endothelium-Specific GTP Cyclohydrolase I Overexpression Attenuates Blood Pressure Progression in Salt-Sensitive Low-Renin Hypertension

Yan-Hua Du MD, Yong-Yuan Guan MD, Nicholas J. Alp MD, Keith M. Channon MD, and Alex F. Chen MD, PhD^*

From the Departments of Pharmacology and Neurology (Y.-H.D., A.F.C.), Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing; Department of Pharmacology (Y.-H.D., Y.-Y.G.), Sun Yat-Sen University, Guangzhou, China; and Department of Cardiovascular Medicine (N.J.A., K.M.C.), John Radcliffe Hospital, Oxford University, Oxford, United Kingdom.

^* To whom correspondence should be addressed. E-mail: chenal{at}msu.edu.

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 (100-µm 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.

Key words: GTP cyclohydrolase • 5,6,7,8-tetrahydrobiopterin • oxidative stress • mesenteric arteries • hypertension

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Clinical Summaries
Circulation 2008 117: 987-989. [Extract] [Full Text]

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