CRP as a biomediator of atherosclerosis and its intracellular signaling

CRP作为动脉粥样硬化的生物介质及其细胞内信号传导

基本信息

批准号：
17590725
负责人：
ITO Masaaki
金额：
$ 2.24万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590725/
关键词：
CRP Rho Rho-kinase endothelial cell PAI-1 glucose NF-_KB 血管内皮細胞

项目摘要

Recently it has become evident that C-reactive protein (CRP) has direct proatherothrombotic effects on vascular cells. We examined the direct effects of CRP on cultured bovine endothelial cells (BAEC) and investigated its underlying signaling.Incubation of BAEC with human recombinant CRP induced a significant increase in PAI-1 expression. Stimulation of BAEC with CRP significantly increased small GTPase RhoA activation. Pretreatment with TAT-C3 (RhoA inhibitor) and Y-27632 (Rho-kinase inhibitor) significantly inhibited CRP-induced PAI-1 expression. NF-_kB activity was markedly enhanced by CRP and pretreatment with Y-27632 inhibited its activation. Parthenolide, SN50 and BAY 11.7082 (NF-_KB inhibitors) significantly blocked CRP-mediated PAI.1 expression. These data suggested that CRP activates Rho/Rho-kinase signaling, which in turn activates NF-_KB activity, resulting in PAI-1 expression in BAEC. These observations provide evidence for the possible involvement of Rho/Rho-kinase signaling in CRP-induced atherothrombogenesis.The expression of PAI.1 was also increased in BAEC by the stimulation with high concentration of glucose (23 mM). Similar to the stimulation with CRP, stimulation with high glucose significantly increased RhoA activation and pretreatment with Y-27632 significantly blocked high glucose-induced PAI-1 expression. NF-_KB activity was also significantly enhanced by high glucose, and pretreatment with Y-27632 inhibited high glucose-induced PAI-1 expression. NF-_KB inhibitors significantly blocked high glucose-mediated PAI-1 expression. These data suggested that high glucose-induced PAI-1 expression in endothelial cells is mediated by NF-_KB activation through the Rho/Rho-kinase pathway. Inhibition of Rho/Rho-kinase signaling might be a novel target for diabetes and metabolic syndrome.

最近，C反应蛋白（CRP）对血管细胞具有直接的促动脉粥样硬化作用已变得很明显。我们检测了 CRP 对培养的牛内皮细胞 (BAEC) 的直接影响，并研究了其潜在的信号传导。将 BAEC 与人重组 CRP 一起孵育可诱导 PAI-1 表达显着增加。用 CRP 刺激 BAEC 显着增加小 GTP 酶 RhoA 的激活。 TAT-C3（RhoA 抑制剂）和 Y-27632（Rho 激酶抑制剂）预处理显着抑制 CRP 诱导的 PAI-1 表达。 CRP 显着增强了 NF-_kB 活性，而 Y-27632 预处理抑制了其激活。小白菊内酯、SN50 和 BAY 11.7082（NF-_KB 抑制剂）显着阻断 CRP 介导的 PAI.1 表达。这些数据表明，CRP 激活 Rho/Rho 激酶信号传导，进而激活 NF-_KB 活性，导致 BAEC 中 PAI-1 表达。这些观察结果为Rho/Rho激酶信号传导可能参与CRP诱导的动脉粥样硬化血栓形成提供了证据。在高浓度葡萄糖(23 mM)的刺激下，BAEC中PAI.1的表达也增加。与 CRP 刺激类似，高葡萄糖刺激显着增加 RhoA 激活，Y-27632 预处理显着阻断高葡萄糖诱导的 PAI-1 表达。高糖也显着增强了 NF-_KB 活性，Y-27632 预处理可抑制高糖诱导的 PAI-1 表达。 NF-_KB抑制剂显着阻断高葡萄糖介导的PAI-1表达。这些数据表明，高葡萄糖诱导的内皮细胞中 PAI-1 表达是通过 Rho/Rho 激酶途径由 NF-_KB 激活介导的。抑制 Rho/Rho 激酶信号传导可能是糖尿病和代谢综合征的新靶点。