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Progress of the study of rho-kinase and future perspective of the inhibitor Tawara S; Shimokawa HYakugaku Zasshi 2007[Mar]; 127 (3): 501-14Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in VSMC proliferation, cell migration, and gene expression. Two isoforms of Rho-kinase encoded by two different genes have been identified: ROCK1 and ROCK2. These isoforms are ubiquitously expressed, but with preferential expression of ROCK2 in the brain and skeletal muscle. The expression of Rho-kinase itself is mediated by the protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At the cellular level, Rho-kinase mediates VSMC contraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. Rho-kinase also upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, while it downregulates endothelial nitric oxide synthase and inhibits insulin signaling. Rho-kinase activity regulates major morphogenetic events during embryonic development through cell migration, differentiation, and axis formation. In animal and clinical studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and ischemia/reperfusion injury. Fasudil, a selective Rho-kinase inhibitor developed in Japan, is effective for the treatment of a wide range of cardiovascular diseases, with reasonable safety. Thus Rho-kinase is an important therapeutic target in cardiovascular medicine. This review summarizes the recent progress in the study of Rho-kinase and addresses future perspectives of Rho-kinase inhibitors.|*Drug Design[MESH]|*Enzyme Inhibitors[MESH]|1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/therapeutic use[MESH]|Animals[MESH]|Cardiovascular Diseases/drug therapy/etiology[MESH]|Cell Proliferation[MESH]|Forecasting[MESH]|Humans[MESH]|Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors/physiology[MESH]|Muscle Contraction[MESH]|Muscle, Smooth, Vascular/cytology/physiology[MESH]|NF-kappa B/physiology[MESH]|Organogenesis[MESH]|Protein Kinase C/physiology[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors/physiology[MESH]|Signal Transduction[MESH]|rho GTP-Binding Proteins[MESH]|rho-Associated Kinases[MESH] |
