P2Y12-cAMP-CREB信号在动脉粥样硬化中调控平滑肌细胞定向趋化及转化

It is reported that antiplatelet drug clopidogrel (P2Y12 antagonist) has antiatherosclerotic potential, which may be caused by the blockade of P2Y12 receptor on vascular smooth muscle cells (VSMC). However, the molecular mechanisms remain elusive. Our preliminary data show that atherosclerotic associated factor ox-LDL could induce the high expression of P2Y12 receptor on VSMC. Activation of P2Y12 mediates the directed migration of vascular smooth muscle cells and its transformation to foam cells. These results indicate that high expression of P2Y12 receptor on VSMCs is closely related to the progression of atherosclerosis. In the present project, we will use gene knockout mice, ChIP, immunflurescence, HPLC, and other methods to verify our hypothesis. Firstly, we will verify that VSMC P2Y12 receptor induces MMP-2 expression by cAMP-CREB signaling, degradating extracellular matrix, and enhancing the migration ability of VSMC. Meanwhile, P2Y12 receptor mediates the directed migration of VSMC to the core of plaque by mismatching chemotactic factor SDF-1, which macrophage secretes in the plaque core. On the other hand, P2Y12 receptor downregulates the expression of ABCA1 by cAMP-CREB signaling, mediating the transformation of VSMC to foam cells in the plaque core. This project will elucidate the molecular mechanisms of VSMC P2Y12 receptor in the progression of atherosclerosis.

研究表明抗血小板药物氯吡格雷（P2Y12受体拮抗剂）具有抗动脉粥样硬化（AS）的作用，可能与血管平滑肌细胞（VSMC）上P2Y12受体有关，但其机制不清。我们发现：AS相关因子诱导VSMC高表达P2Y12受体，后者诱导VSMC定向趋化及向泡沫细胞转化，提示VSMC上P2Y12受体与斑块进展相关。本项目拟采用基因敲除小鼠、ChIP、免疫荧光、HPLC等技术，阐明VSMC上P2Y12受体在AS进展中的关键作用及分子机制，验证工作假说：在AS进展中，VSMC上高表达的P2Y12受体，能通过cAMP-CREB信号通路，一方面诱导基质金属蛋白酶MMP-2表达，降解胞外基质，游离VSMC，同时P2Y12受体能“错义”识别斑块核心巨噬细胞产生的趋化因子SDF-1，使游离的VSMC定向趋化至斑块核心；另一方面通过抑制胆固醇逆转运体ABCA1表达，使趋化至斑块核心的VSMC转化成泡沫细胞，最终促进斑块进展。

研究表明抗血小板药物氯吡格雷（P2Y12受体拮抗剂）具有抗动脉粥样硬化（AS）的作用，可能与血管平滑肌细胞（VSMC）上P2Y12受体有关，但其机制不清。本项目采用基因敲除小鼠、蛋白组学、免疫荧光等技术，阐明VSMC上P2Y12受体在AS形成和进展中的关键作用及分子机制，我们发现：1.AS相关因子（ox-LDL）诱导VSMC高表达P2Y12受体，高表达的P2Y12受体活化后通过cAMP/PKA信号调控cofilin脱磷酸化和F-actin的解聚，从而促进VSMCs迁移参与斑块形成；2.VSMC上高表达的P2Y12受体，通过PI3K/AKT/mTOR途径抑制VSMCs来源的泡沫细胞自噬，促进VSMCs形成泡沫细胞和斑块进展；3.血清sLRP1可作为一种生物标记物，反映动脉粥样硬化斑块中P2Y12受体水平，决定患者是否选择P2Y12受体抑制剂作为治疗药物。同时我们还结合既往研究和我们的成果，创新性提出对于动脉粥样硬化型缺血性卒中患者，P2Y12受体阻断剂二级预防效果可能更好。本研究系统阐述了血管平滑肌细胞（VSMC）上P2Y12受体在动脉粥样硬化中的作用和分子机制，发现了动脉粥样硬化治疗新靶点，具有重要的科学意义和临床价值。