on December 18, 2008
Published online before print December 18, 2008, doi: 10.1161/ATVBAHA.108.181024
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Submitted on November 13, 2008
Accepted on December 4, 2008
Endothelial Nitric Oxide Synthase Inhibits G12/13 and Rho-Kinase Activated by the Angiotensin II Type-1 Receptor. Implication in Vascular Migration
Hiroyuki Suzuki ;
From the Cardiovascular Research Center, Department of Physiology (H. Suzuki, K.K., H. Shirai, K.E., S.H., A.H., K.I., M.V.A., S.E.), the Department of Pharmacology (E.B.), and Fels Institute for Cancer Research and Molecular Biology (D.N.D.), Temple University School of Medicine, Philadelphia, Pa; the Department of Pathology (L.N.S., T.A.F.), Duke University Medical Center, Durham, NC; and the Department of Biochemistry (G.D.F.), Vanderbilt University School of Medicine, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: seguchi{at}temple.edu.
Background—Although, endothelial nitric oxide (NO) synthase (eNOS) is believed to antagonize vascular remodeling induced by the angiotensin II (AngII) type-1 receptor, the exact signaling mechanism remains unclear.
Methods and Results—By expressing eNOS to vascular smooth muscle cells (VSMCs) via adenovirus, we investigated a signal transduction mechanism of the eNOS gene transfer in preventing vascular remodeling induced by AngII. We found marked inhibition of AngII-induced Rho/Rho-kinase activation and subsequent VSMC migration by eNOS gene transfer whereas Gq-dependent transactivation of the epidermal growth factor receptor by AngII remains intact. This could be explained by the specific inhibition of G12/13 activation by eNOS-mediated G12/13 phosphorylation.
Conclusion—The eNOS/NO cascade specifically targets the Rho/Rho-kinase system via inhibition of G12/13 to prevent vascular migration induced by AngII, representing a novel signal cross-talk in cardiovascular protection by NO.
Key words: angiotensin II • vascular smooth muscle • G protein • nitric oxide synthase
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