高密度脂蛋白及其模拟肽对内质网应激途径介导的巨噬细胞泡沫化及凋亡的调节作用机制

Macrophage derived foam cell formation and apoptosis in artery endothelium contribute to the development of atherosclerosis (AS) and the emerging of instable plaques. Our previous study in the past 2 years demonstrated that oxidized low density lipoprotein (ox-LDL) can induce macrophage foam cell formation and apoptosis via endoplasmic reticulum stress (ERS) pathway. But the effect of high density lipoprotein (HDL) which has multiple antiatherogenic functions on the ERS-mediated macrophage foam cell formation and apoptosis is still unknown. Furthermore, in the case of glucose and lipid metabolic disturbance such as diabetes and metabolic syndrome, HDL can be oxidized and glycated, then lose the antiatherogenic functions, but the underlying mechanism remains unclear. Therefore we assume that normal and modified HDL may have different effects on ERS-mediated macrophage foam cell formation and apoptosis, thereby suppress or promote the formation and instability of atherosclerotic plaques. In this study, we apply in vitro model of ERS-mediated macrophage foam cell formation and apoptosis induced by ox-LDL and AS model of apolipoprotein E-/- mice with hyperlipidemia or hyperglycemia to study the regulatory effect of different kinds of HDL and its mimic peptide on ERS-mediated macrophage foam cell formation and apoptosis and its molecular mechanism and explore their impact on AS development and stability. Meanwhile the key cellular signal and cell surface receptors involved in the regulation of HDL and its mimic peptide on ERS are identified by the technology of gene silencing, etc. This work will provide a new perspective for strategy of improving clinical cardiovascular events targeted HDL.

动脉内膜巨噬细胞泡沫化和凋亡是粥样硬化（AS）和易损斑块形成的主要病理过程之一。我们的前期工作证明氧化低密度脂蛋白（ox-LDL）可通过内质网应激（ERS）途径诱导巨噬细胞泡沫化和凋亡。但高密度脂蛋白（HDL）在巨噬细胞泡沫化和凋亡的ERS途径中的作用尚不清楚。而在糖脂代谢紊乱条件下，HDL因被氧化和糖化修饰而失去抗AS作用的分子机制迄今知之甚少。因此我们设想HDL在正常和修饰条件下可能对ERS介导的巨噬细胞泡沫化和凋亡产生不同影响，从而抑制或促进动脉斑块及其脆性的形成。本项目拟采用ox-LDL诱导的ERS巨噬细胞泡沫化和凋亡的体外模型以及高脂、高糖的载脂蛋白E缺陷小鼠的AS模型，研究不同形式的HDL及其模拟肽对巨噬细胞ERS介导的泡沫化和凋亡途径的调节作用及分子机制，探讨其对AS进展及稳定性的影响。同时应用基因沉默技术等明确参与HDL和模拟肽调节ERS反应的关键细胞内信号和表面受体蛋白。

氧化低密度脂蛋白(ox-LDL)诱导的巨噬源性泡沫细胞和血管内皮细胞的损伤与凋亡在动脉粥样硬化发生发展中起关键作用；高密度脂蛋白(HDL)具有胆固醇逆向转运、抗炎、抗氧化等抗动脉粥样硬化(AS)作用，但其功能可能因氧化、糖基化修饰而降低、甚至呈现出促AS作用，但脂蛋白异常尤其是HDL氧化和糖基化修饰致AS的内质网应激机制尚未完全阐明。本课题在ox-LDL/ox-HDL诱导的巨噬源性泡沫细胞模型、内皮细胞损伤模型和衣霉素（TM）诱导的RAW264.7细胞内质网应激（ERS）模型以及apoE-/-小鼠动脉粥样硬化模型上，探讨了内质网应激、氧化应激、NF-κB-死亡受体等信号途径在动脉粥样硬化发病及防治机制中的作用。研究结果显示：（1）内质网应激信号途径介导ox-LDL诱导的巨噬源性泡沫细胞形成和凋亡；(2) ox-HDL通过TLR4介导的内质网应激-CHOP信号途径诱导巨噬细胞凋亡; (3) 银屑病降低高密度脂蛋白抗氧化和抗炎功能; (4) 走跑运动改善代谢综合征患者高密度脂蛋白抗炎功能；(5) 载脂蛋白AI模拟肽D4F通过抑制内质网应激凋亡途径、氧化应激和NF-κB-Fas/FasL途径减轻巨噬源性泡沫细胞凋亡；(6) D4F通过上调血管内皮细胞色素上皮衍生因子表达减轻ox-LDL诱导的血管内皮细胞损伤;（7）蜂胶醇提物和大蒜素通过抑制ERS凋亡途径减轻ox-LDL诱导的巨噬细胞凋亡；（8）自噬通过抑制CHOP表达减轻ox-LDL诱导的巨噬细胞凋亡。上述研究结果表明内质网应激、NF-κB-Fas/FasL等信号途径参与ox-LDL/ox-HDL所致AS的发生发展，而走跑运动、载脂蛋白AI模拟肽D4F、蜂胶黄酮及大蒜素可通过改善HDL功能，抑制该信号途径减轻AS进展，因此修饰脂蛋白，内质网应激、NF-κB-Fas/FasL等信号途径有望成为AS防治的新的干预靶点。

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