title: Thrombin induces MCP-1 expression through Rho-kinase and subsequent p38MAPK/NF-κB signaling pathway activation in vascular endothelial cells.
abstract: Thrombin has been shown to increase expression of chemokines such as monocyte chemoattractant protein 1 (MCP-1) in endothelial cells, leading to the development of atherosclerosis. However, the precise mechanism of this induction remains unknown. In the present study, we investigated whether the small G protein RhoA, and its effector, Rho-kinase are involved in MCP-1 induction by thrombin in endothelial cells. Y-27632, a specific Rho-kinase inhibitor, potently inhibited MCP-1 induction by thrombin. Y-27632 significantly decreased the chemotactic activity of thrombin-stimulated supernatants of endothelial cells on monocytes. Importantly, fasudil, a specific Rho-kinase inhibitor, attenuated MCP-1 gene expression in the aorta of db/db mice. Y-27632 attenuated thrombin-mediated phosphorylation of p38MAPK and p65, indicating that Rho-kinase mediates thrombin-induced MCP-1 expression through p38MAPK and NF-κB activation. Our findings demonstrate that the Rho/Rho-kinase signaling pathway plays a critical role in thrombin-mediated MCP-1 expression and function, and suggest that Rho/Rho-kinase may be an important target in the development of new therapeutic strategies for atherosclerosis.
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan. daijika@jikei.ac.jp
authors.forename: Daiji
authors.initials: D
authors.lastname: Kawanami
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Matoba
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Sho
authors.initials: S
authors.lastname: Ishizawa
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yokota
authors.forename: Kazunori
authors.initials: K
authors.lastname: Utsunomiya
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013917:Thrombin / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000577:Amides; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; C049347:fasudil