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(Circulation. 2003;108:1238.)
© 2003 American Heart Association, Inc.

Basic Science Reports

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

Jie-Sheng Zheng, MD; Xiang-Qun Yang, MD, PhD; Keith J. Lookingland, PhD; Gregory D. Fink, PhD; Christian Hesslinger, PhD; Gregory Kapatos, PhD; Imre Kovesdi, PhD; Alex F. Chen, MD, PhD

From the Department of Pharmacology and Toxicology and the Neuroscience Program, Michigan State University, East Lansing, Mich (J.-S.Z., X.-Q.Y., K.J.L., G.D.F., A.F.C.); Department of Neurosurgery, the First Affiliate Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R. China (J.-S.Z.); Altana Pharma AG, Konstanz, Germany (C.H.); Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Mich (G.K.); and GenVec, Inc, Gaithersburg, Md (I.K.)

Correspondence to Alex F. Chen, MD, PhD, FAHA, Department of Pharmacology and Toxicology and the Neuroscience Program, B403 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. E-mail chenal{at}msu.edu

Original received June 26, 2003; revision received July 17, 2003; accepted July 17, 2003.

Background— 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.

Methods and Results— 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 ET_A 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.

Conclusions— These results indicate that a BH₄ deficiency resulting from ET-1–induced O₂^- via an ET_A/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.

Key Words: gene therapy • endothelin • antioxidants • nitric oxide • free radicals

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