Published online before print February 11, 2008, doi: 10.1161/CIRCULATIONAHA.107.748236
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(Circulation. 2008;117:1045-1054.)
© 2008 American Heart Association, Inc.
Hypertension |
Endothelium-Specific GTP Cyclohydrolase I Overexpression Attenuates Blood Pressure Progression in Salt-Sensitive Low-Renin Hypertension
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.
Correspondence to Alex F. Chen, MD, PhD, FAHA, Associate Professor, B403 Life Sciences Bldg, Michigan State University, East Lansing, MI, 48824-1317. E-mail chenal{at}msu.edu
Received March 6, 2007; accepted December 14, 2007.
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.
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