Endothelial Nitric Oxide Synthase Inhibits G12/13 and Rho-Kinase Activated by the Angiotensin II Type-1 Receptor: Implication in Vascular Migration

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 29; no. 2; pp. 217 - 224
• Main Authors: Suzuki, Hiroyuki, Kimura, Keita, Shirai, Heigoro, Eguchi, Kunie, Higuchi, Sadaharu, Hinoki, Akinari, Ishimaru, Kazuhiro, Brailoiu, Eugen, Dhanasekaran, Danny N, Stemmle, Laura N, Fields, Timothy A, Frank, Gerald D, Autieri, Michael V, Eguchi, Satoru
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2009; Lippincott Williams & Wilkins
• Subjects: Adenoviridae - genetics; Angiotensin II - metabolism; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cattle; Cell Movement; Cells, Cultured; Coronary heart disease; Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - enzymology; Genetic Vectors; GTP-Binding Protein alpha Subunits, G12-G13 - metabolism; Heart; Medical sciences; Muscle, Smooth, Vascular - enzymology; Myocytes, Smooth Muscle - enzymology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Phosphorylation; Protein Phosphatase 1 - metabolism; Rats; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Epidermal Growth Factor - metabolism; rho-Associated Kinases - metabolism; Signal Transduction; Time Factors; Transduction, Genetic; vascular smooth muscle; Enzyme; Peptide hormone; Smooth muscle; Cardiovascular disease; Nitric-oxide synthase; Vascular disease; Octapeptide; Renin angiotensin system; Atherosclerosis; Oxidoreductases; nitric oxide synthase; Angiotensin II; G protein
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.108.181024

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.