连接蛋白43对低剪切应力诱导内皮细胞间质转化的调节作用

项目名称： 连接蛋白43对低剪切应力诱导内皮细胞间质转化的调节作用

项目编号： No.81200206

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 张宗棨

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 低剪切应力是重要的促动脉粥样硬化因素；内皮-间质转化是动脉粥样硬化发生的重要机制。前期研究发现，低剪切应力能诱导内皮间质转化，且间隙连接蛋白43参与这一过程。因此，本研究提出"Cx43调节低剪切应力诱导血管内皮间质转化"研究假说。为验证这一假说，本研究拟通过体内实验：建立Cx43半敲除小鼠诱导颈动脉低剪切应力模型，在高脂饮食或普通饮食喂养条件下，检测不同剪切应力部位血管内皮EndMT及纤毛形成；通过体外实验：利用基因过表达或siRNA基因沉默、信号通路蛋白抑制等方法，观察Cx43过表达或低表达的小鼠颈动脉内皮细胞，在不同剪切应力下内皮间质转化、纤毛形成及相关信号通路变化，以期阐明Cx43对低剪切应力诱导内皮间质转化的调节作用及其机制，为动脉粥样硬化发生机制提供新的认识，也为临床干预低剪切应力促动脉粥样硬化提供潜在治疗靶点。

中文关键词： 血管内皮细胞；血管平滑肌细胞；剪切应力；间质转化；连接蛋白43

英文摘要： Low shear stress independently contributes to atherogenesis. Endothelial-to-mesenchymal transition(EndMT) plays an important role in atherogenesis. Our preliminary experiments showed that low shear stress induced EndMT in mice vascular endothelial cells, in which connexin 43(Cx43) is involved. Therefore, we proposed the regulation of Cx43 in low shear stress-induced EndMT. To demonstrate this hypothesis, we design the present study: 1) In vivo, after the induction of low shear stress in left common carotid artery of Cx43+/- mice, feeded by normal or high-fat food, EndMT in vascular endothelial cells is detected at predeterminated time intervals. And at the same time, cilia will be also examined to explore the correlation between primary cilia and Cx43 expression. 2)In vitro, mice vascular endothelial cells were isolated from carotid artery.By using virus transfection to induced overexpressions of Cx43 and using siRNA trasfection to silence the expressions of Cx43, the cells underwent low shear stress stimulus to induce EndMT treated with distinct signaling inhibitors,and then EndMT was explored. The cellular primary cilia and changes of signaling mediators were detected, too. It is supposed to clrify the effects of Cx43 on low shear stress-induced EndMT and the underlying mechanisms. The results from the present

英文关键词： vascular endothelial cells；vascular smooth muscle cells；shear stress；mesenchymal transition；connexin 43