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

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.

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。

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。氧化型低密度脂蛋白（oxLDL）是最重要的致AS脂质成分，还可诱导细胞内的炎症反应过程，因而在脂质-炎症交互式调节反应中起到关键的作用。清道夫受体CD36是介导细胞内吞oxLDL的主要受体，是否其参与了VSMC的炎症表型转化？又有哪些具体的分子机制？是我们关注的重点问题。我们推测，oxLDL与VSMC细胞膜上的CD36受体结合，通过与TLR4之间的相互作用，激活下游炎症信号通路，诱导炎性细胞因子的产生和释放，促进VSMC转化为炎症表型。据此本项目展开以下研究内容：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。结果发现：①证实oxLDL可促进VSMC的炎症表型转化，并促进AS病变的发生发展；②发现清道夫受体CD36介导了oxLDL促进VSMC炎症表型转化的作用，并在AS病灶形成中发挥重要作用；③CD36可与胞膜上的TLR4发生相互作用，并通过活化下游的MyD88而诱导VSMC内的炎性反应，并促进细胞转化为炎症表型。本项目从VSMC的炎症表型转化这一新的角度，阐释了AS的发生机制，并加深了对VSMC表型转化的认识，确立了CD36作为促进VSMC炎症表型和细胞内脂质聚积的关键分子及其在AS预防中的关键作用，从而为AS的防治提供了新的思路。