Humanin对血管内皮细胞氧化低密度脂蛋白的降解调控及分子机制研究

氧化低密度脂蛋白（ox-LDL）在血管内皮细胞（VEC）的异常聚集是动脉粥样硬化（AS）进程中关键起始环节，这与其胞内降解障碍有关。自噬是机体降解细胞内异常物质的主要途径，我们发现暴露于ox-LDL的VEC存在自噬流障碍，自噬激活剂雷帕霉素可以通过修复自噬流促进细胞内脂质降解保护VEC、延缓AS进程，然较大的副作用限制了其在临床应用。新近研究发现内源性小分子多肽Humanin（HN）在AS中具有保护VEC、延缓斑块进展的作用，有望成为新型抗AS药物。我们前期研究显示HN可减少ox-LDL在VEC的聚集，对ox-LDL引起的自噬流障碍有修复作用。本课题将运用活细胞工作站、细胞转染和基因敲减等方法从分子、细胞和动物水平系统性研究HN对ox-LDL在VEC的自噬性降解调控和延缓AS进展的作用及可能分子机制。研究有助于明确HN的血管保护作用，对新药研发具有重要意义。

Abnormal accumulation of oxidized low-density lipoprotein (ox-LDL) in the vascular endothelial cell (VEC) is a critical initiating stage in the development of atherosclerosis (AS), which is related to the degradation disorders of ox-LDL in VECs. Autophagy is an important pathway for abnormal materials degradation in cells. In our previous study, it has been found that impaired autophagic flux occurred in VEC in the presence of ox-LDL; while rapamycin, an autophagy activator, could promote lipid degradation and protect VEC as well as delay the progression of AS by enhancing ox-LDL-induced impaired autophagic flux. However, the serious adverse effects with rapamycin limit its clinic treatment. Humanin (HN), a newly discovered endogenous small polypeptide, could protect VEC and delay plaque progression, which is expected to become a novel anti-AS drug. Our previous study found that ox-LDL could lead to autophagy dysfunction in VEC, while HN could enhance ox-LDL-induced impaired autophagic flux and reduce intracellular lipid content. Through the methods of live cell imaging, cell transfection and gene knockdown et al., we will systematically explore the regulation and mechanisms of HN promoting ox-LDL autophagic degradation in VECs and preventing AS progression. This study is important for a better understand of the protective role of HN in the development of AS.