丛生蛋白Clusterin通过调控自噬抑制血管内皮细胞焦亡延缓糖尿病动脉粥样硬化的作用及机制研究

动脉粥样硬化（AS）相关心血管事件是糖尿病死亡的首要原因，糖尿病AS病理特点为血管内皮损伤发生早、损伤范围广且严重，目前缺乏有效治疗措施。我们前期研究发现丛生蛋白（CLU）可能成为抑制血管内皮损伤，改善糖尿病AS发生发展的关键靶点：糖尿病AS患者血浆CLU水平反馈性升高；过表达CLU能够激活内皮细胞AMPK，进而调控细胞自噬，降低促进AS发展的焦亡相关蛋白NLRP3和IL-1β的表达，而干扰CLU受体LRP2的表达后，CLU作用消失。据此提出假说：CLU结合LRP2后，通过激活AMPK调控细胞自噬抑制内皮细胞焦亡，从而缓解糖尿病AS的发生发展。本研究将建立糖尿病AS小鼠模型，通过分析敲除及过表达CLU对糖尿病AS的影响，确证CLU在糖尿病AS中的作用；在体内外模型中，通过抑制LRP2和AMPK的表达，分析CLU调控细胞自噬和焦亡的机制，从而为探索糖尿病AS病理机制及药物靶点发现提供新思路。

The leading cause of mortality in type 2 diabetes mellitus is atherosclerotic cardiovascular complications. Serious and extensive vascular endothelial injury occurs early in diabetic atherosclerosis. However, the pathogenesis of diabetic atherosclerosis remains indistinct, and the effective therapeutic drugs remain deficient. The results of our previous studies demonstrated that clusterin is a potential therapeutic target in diabetic atherosclerosis. Adenoviral clusterin over-expression could activate AMPK, modulate autophagy, and decrease the expression of NLRP3 and IL-1β, while the inhibition of low density lipoprotein receptor related protein 2 (LRP2) offset the effect of clusterin overexpression. Meanwhile, we found that the plasma clusterin level showed a feedback increasing trend in diabetes mellitus complicated with atherosclerosis. Thus, we proposed that “clusterin attenuates diabetic atherosclerosis by inhibiting pyroptosis in endothelial cells via modulating autophagy”. The roles of clusterin in diabetic atherosclerosis will be investigated using clusterin over-expressed and knock out mice. The inhibitor of AMPK and LRP2 knock out mice were used to investigate the related mechanisms. The research will contribute to understanding the mechanism of diabetic atherosclerosis, and provide important basis for discovering drugs to prevent and treat diabetic atherosclerosis.