on July 7, 2005
Published online before print July 7, 2005, doi: 10.1161/01.ATV.0000176193.83629.c8
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Submitted on May 3, 2005
Accepted on June 24, 2005
Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine
Hiroaki Shimokawa * and Akira Takeshita
From the Department of Cardiovascular Medicine (H.S., A.T.) and the Kyushu University COE Program on Lifestyle-Related Diseases (H.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka; and Japan Science and Technology Agency (H.S.), CREST, Tokyo, Japan.
Abstract--Rho-Kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-
B pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.
Key words: cardiovascular disease • Rho • small G proteins • signal transduction • Rho-kinase
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