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

نویسندگان

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

Chronic inhibition of endothelial NO synthesis by the administration of N-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 factor1 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. (Hypertension. 2002;39:245-250.)

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تاریخ انتشار 2002