糖化vimentin促进动脉粥样硬化发生和机制研究

项目名称： 糖化vimentin促进动脉粥样硬化发生和机制研究

项目编号： No.81470469

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 丁风华

作者单位： 上海交通大学

项目金额： 72万元

中文摘要： 糖尿病时动脉粥样硬化发生率高但机制未完全阐明。为比较糖尿病冠状动脉粥样硬化和糖尿病无明显动脉粥样硬化血管组织培养液中蛋白成分的差异，用终末糖化产物（AGEs）受体（RAGE）-His-磁珠行免疫沉淀-质谱检测，发现并证实粥样硬化组织中糖化vimentin含量显著升高。前期研究和文献中，vimentin能被糖化修饰。我们发现AGEs-vimentin使内皮细胞中骨架纤维聚集。AGEs增加细胞分泌糖化vimentin。AGEs-vimentin促进内皮细胞表达粘附分子，及单核巨噬细胞-内皮细胞粘附；诱导巨噬细胞表达炎症因子和金属蛋白酶，促进吞脂和迁移效应。综合文献，AGEs-vimentin又可能是Dectin-1、NOD2、RAGE和TLR2等受体的配体。后续将采用上述基因修饰小鼠，以体内体外实验探讨AGEs-vimentin对动脉粥样硬化发生的影响，寻找致病作用位点，阐明相关机制。

中文关键词： 晚期糖基化终末产物；vimentin；动脉粥样硬化；模式识别受体

英文摘要： The mechanism of accelerated atherosclerosis in diabetes remains fully unknown. To detect the differences of protein profiles of atherosclerotic and non-atherosclerotic tissue in cell culture between atherosclerotic and non-atherosclerotic vascular tissue in diabetes, we performed the mass spectrometric analysis using receptor for advanced glycated end products (RAGE)-his-tag fusion protein and found the significant increase of glycated vimentin in atherosclerotic tissue. Previous studies including ours have demonstrated that advanced glycation end products (AGEs) of vimentin (AGEs-vimentin) can promote the aggregation of cytoskeleton fiber in endothelial cells. AGEs-vimentin increases the adhesion molecule expression in endothelial cell, promotes monocyte and endothelial cell adhesion, induces inflammatory cytokines and matrix metalloproteinase expression in macrophages and activate macrophage migration and phagocytotic activity. According to previous reports, AGEs-vimentin is a potential ligand for several pattern recognition receptors, such as Dectin-1, NOD2, RAGE and TLR2. We will test and verify our hypothesis, and explore the AGE-vimentin in pathogenesis of atherosclerosis by using above-mentioned gene knock-out mice in vivo and in vitro.

英文关键词： advanced glycation end products;vimentin;atherosclerosis;pattern recognition receptor