PCSK9介导巨噬细胞凋亡在稳定动脉粥样硬化斑块中的作用和机制研究

项目名称： PCSK9介导巨噬细胞凋亡在稳定动脉粥样硬化斑块中的作用和机制研究

项目编号： No.81200208

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： 戴金

作者单位： 浙江中医药大学

项目金额： 23万元

中文摘要： 低密度脂蛋白（LDL）是动脉粥样硬化（AS）形成和斑块不稳定的关键。他汀类药物引起的前蛋白转化酶枯草溶菌酶9（PCSK9）浓度依赖性上调直接减弱了其降LDL的效应，PCSK9表达上调后能负相关的使LDL受体（LDLR）表达下调，减弱对血浆胆固醇的清除，因此抑制PCSK9表达对AS防治有重要意义。在前期工作中，申请者发现PCSK9在AS斑块内表达显著升高，推测PCSK9可能影响斑块稳定性，但具体机制尚待研究。我们采用高脂饲喂APOE-/-小鼠AS模型，观察PCSK9抑制剂对斑块，斑块巨噬细胞、LDLR、Fas/FasL的影响；然后采用人主动脉平滑肌细胞和巨噬细胞，结合PCSK9 siRNA和LDLR siRNA，运用平滑肌细胞培养液干预巨噬细胞，明确PCSK9在影响斑块稳定性的具体机制。本项目完成将丰富PCSK9在AS斑块稳定性方面的理论，为PCSK9抑制剂联合他汀降脂、抗AS提供理论基础。

中文关键词： 前蛋白转化酶枯草溶菌酶9；动脉粥样硬化；巨噬细胞凋亡；；

英文摘要： Low-density lipoprotein (LDL) plays a major role in the formation of atherosclerosis(AS) and plaque instability.Statins is known to decrease the circulating LDL, but the concentration- dependent incrase of Proprotein Convertase Subtilisin/Kexin type 9(PCSK9) caused by statins can directly reduce the effect of LDL reduction. Overexpression of PCSK9 is found to inversely downregulate the low-density lipoprotein receptor (LDLR) and reduce the clearance of plasma cholesterol, so to inhibit PCSK9 overexpression is significant in the preventation and treatment of AS. In pre-study, we find PCSK9 is significantly increased in atherosclerotic plaques, so that we presume PCSK9 could influence the stability of atherosclerotic plaques, but the exact mechanisms by which PCSK9 effects the stability of atherosclerotic plaques are still unclear. In this study, we firstly establish a APOE-/- mouse atherosclerotic model by high-cholesterol diet to observe the influence of PCSK9 inhibitor on atherosclerotic plaques, macrophages, LDLR and Fas/FasL. Then we use conditioned media from human aortic smooth muscle cells to intervent macrophages, combind with PCSK9 siRNA and LDLR siRNA, to make sure the exact mechanisms in PCSK9 affecting plaque's stability. This study result would richen the theory of PCSK9 in atherosclerotic plaques st

英文关键词： Proprotein Convertase Subtilisin/Kexin type 9；atherosclerosis；macrophage apoptosis；；