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(Hypertension. 2002;39:245.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats

Chu Kataoka; Kensuke Egashira; Shujiro Inoue; Masao Takemoto; Weihua Ni; Masamichi Koyanagi; Shiro Kitamoto; Makoto Usui; Kozo Kaibuchi; Hiroaki Shimokawa; Akira Takeshita

From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University (C.K., K.E., S.I., M.T., W.N., M.K., S.K., M.U., H.S., A.T.), Fukuoka, Japan; and Division of Signal Tranduction, Nara Institute of Science and Technology (K.K.), Ikoma, Japan.

Correspondence to Kensuke Egashira, MD, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Chronic inhibition of endothelial NO synthesis by the administration of N^G-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 expression) as well as subsequent arteriosclerosis. The small GTPase Rho controls cell adhesion, motility, and proliferation and is activated by several growth factors such as angiotensin II. We investigated the effect of a specific inhibitor of Rho-kinase, Y-27632, in rats treated with L-NAME to determine the role of the Rho/Rho-kinase pathway in the development of arteriosclerosis. We found here increased activity of Rho/Rho-kinase after L-NAME administration and its prevention by angiotensin II type 1 receptor blockade. Hydralazine or lecithinized superoxide dismutase (l-SOD) did not affect Rho/Rho-kinase activity. Co-treatment with Y-27632 did not affect the L-NAME-induced increase in cardiovascular tissue ACE activity or L-NAME-induced decrease in plasma NO concentrations, but did prevent the L-NAME-induced early inflammation and late coronary arteriosclerosis. In addition, Y-27632 prevented the increased gene expression of monocyte chemoattractant protein-1 and transforming growth factor-ß1 as well as cardiac fibrosis and glomerulosclerosis. These findings suggest that increased activity of Rho/Rho-kinase pathway mediated via the angiotensin II type 1 receptor may thus be important in the pathogenesis of early vascular inflammation and late remodeling induced by chronic inhibition of NO synthesis. The beneficial effects of Rho-kinase inhibition are not mediated by restoration of NO production. The Rho-kinase pathway could be a new therapeutic target for treatment of vascular diseases.

Key Words: Rho-kinase • arteriosclerosis • remodeling • nitric oxide • angiotensin

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