Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
Biochem Biophys Res Commun. 2011 Aug 12;411(4):798-803. doi: 10.1016/j.bbrc.2011.07.031. Epub 2011 Jul 20.
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.
凝血酶已被证明可增加内皮细胞中趋化因子（如单核细胞趋化蛋白 1（MCP-1）的表达，从而导致动脉粥样硬化的发生。然而，这种诱导的确切机制尚不清楚。在本研究中，我们研究了小 G 蛋白 RhoA 及其效应物 Rho 激酶是否参与了凝血酶诱导的内皮细胞中 MCP-1 的诱导。Rho 激酶的特异性抑制剂 Y-27632 可强烈抑制凝血酶诱导的 MCP-1 的诱导。Y-27632 显著降低了凝血酶刺激的内皮细胞上清液对单核细胞的趋化活性。重要的是，Rho 激酶的特异性抑制剂法舒地尔可减轻 db/db 小鼠主动脉中的 MCP-1 基因表达。Y-27632 可减弱凝血酶介导的 p38MAPK 和 p65 的磷酸化，表明 Rho 激酶通过 p38MAPK 和 NF-κB 的激活来介导凝血酶诱导的 MCP-1 表达。我们的研究结果表明，Rho/Rho 激酶信号通路在凝血酶介导的 MCP-1 表达和功能中起着关键作用，并提示 Rho/Rho 激酶可能是动脉粥样硬化新治疗策略发展的重要靶点。
