动脉粥样硬化中oxLDL/CD36受体介导VSMC炎症表型转化的作用和机制

项目名称： 动脉粥样硬化中oxLDL/CD36受体介导VSMC炎症表型转化的作用和机制

项目编号： No.81471193

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： 张莉莉

作者单位： 中国人民解放军第三军医大学

项目金额： 70万元

中文摘要： 血管平滑肌细胞（VSMC）转化为炎症表型是动脉粥样硬化（AS）的重要环节，其调控机制尚不明确。oxLDL是最重要的致AS脂质成分，还具有促进炎症反应的作用。最近的研究发现巨噬细胞中的清道夫受体CD36在oxLDL诱导下与TLR4和TLR6形成复合物，促进炎性反应。我们推测oxLDL活化VSMC上的CD36可能通过与TLR4结合而启动下游炎性信号通路，诱导VSMC向炎症表型转化。为此本研究拟①应用基因工程技术和ApoE-/-/CD36-/-基因敲除鼠，观察CD36对高脂诱导的AS形成和VSMC炎症表型的影响；②明确oxLDL诱导下VSMC中CD36-TLR4复合物的形成及其对VSMC炎症表型转化的影响；③分别抑制TLR4下游的MyD88和TRIF表达，探讨CD36介导胞内炎性信号传递的具体途径。通过本项目的研究旨在探讨AS病变中VSMC炎症表型转化的调控机制，寻找新的AS防治干预靶点。

中文关键词： 脑血管病；动脉粥样硬化；血管平滑肌细胞；炎症表型

英文摘要： Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays critical role in development of atherosclerosis(AS).VSMCs located in AS lesions display obvious inflammatory phenotype, characterized by expressing some inflammatory cellular markers and releasing variety of inflammtory cytokines including IL-1β, IL-6, TNF-α, MCP-1 and adhesive molecules such as ICAM-1 and VCAM-1, as well as the decreased contractive protein and increased proliferation and migration. It has been reported that oxLDL, a well-established atherogenic oxidized lipid, can induce the inflammatory phenotype in AS. However, the molecular mechanisms remain unclear. Most recently, oxLDL was found to activate scavenger receptor CD36 and then promote the integrate of CD36 with TLR4-TLR6 dimer complex and ultimately induce the inflammatory reaction in macrophage. We speculate that oxLDL may also accelerate the integrate of CD36 with TLR4 in VSMC, and thus initiate the inflammtory signaling pathway inside VSMCs, which results in the inflammatory phenotypic modulation of VSMCs. Herein, we detecte the role of CD36 in AS development and VSMC inflammatory phenotype using both ApoE-/-/CD36-/-mice and genetic engineering technology. Thereafter, we identify the TLR4-CD36 compound in VSMCs, and obseve the potent effect of this CD36-TLR4 compound on VSMC inflammatory phenotypic modulation. Furthermore, molecules that mediate the inflammation signaling downstream of TLRs, including MyD88 and TRIF, will be respectively knockdown to identify the signaling pathway through which CD36 induces the inflammatroy phenotype of VSMCs. We aim to provide further insights into VSMC inflammatory phenotypic modulation in AS lesions, and thus contribute to a better understanding of the development and the pathogenesis of AS.

英文关键词： cerebral vascular disease;atherosclerosis;vascular smooth muscle cell;inflammatory phenotype