Sirt6/Caveolin-1自噬性降解途径在高糖促进LDL穿胞加速动脉粥样硬化形成中的作用及分子干预

糖尿病大血管并发症的基础是动脉粥样硬化（AS）。LDL在内皮细胞中穿胞并沉积于内皮下是AS发生的始动环节。我们前期研究发现高糖可抑制内皮细胞（ECs）中小凹蛋白Caveolin-1自噬性降解促进LDL穿胞，加速AS发生发展。进一步研究发现Caveolin-1可与去乙酰化酶Sirt6相互作用并被其去乙酰化，从而激活Caveolin-1自噬性降解途径，抑制LDL穿胞。本项目将深入研究Sirt6/Caveolin-1自噬性降解途径在高糖促进LDL穿胞加速AS形成中的作用，并分别通过外源过表达Sirt6和导入Caveolin-1 跨膜段（IMD）与自噬标志蛋白LC3B的Caveolin-1结合区段（CBM）复合肽（IMD-CBM），来选择性激活Caveolin-1自噬性降解途径，减少LDL穿胞，干预糖尿病AS的发生发展。研究成果将为糖尿病AS的防治提供新的策略和手段。

Atherosclerosis (AS) is the basis of diabetic macrovascular complications. LDL transcytosis across endothelial cells and deposits under the endothelium is the initiation step of AS. Our previous studies have found that high glucose can inhibit the autophagic degradation of Caveolin-1 and promote LDL transcytosis across endothelial cells ,which in turn accelerates the development of AS. Further research found that Caveolin-1 can be deacetylated by the deacetylase Sirt6, thereby activating Caveolin-1 autophagic degradation pathway and inhibiting LDL transcytosis. In this project, the roles of Sirt6/Caveolin-1 autophagic degradation pathway in high glucose-stimulated LDL transcytosis and the formation of AS will further studying. Meanwhile，by overexpressing Sirt6 or introducing a complex peptide including intramembrane domain (IMD) of Caveolin-1 and Caveolin-1 binding motif (CBM)of the autophagy marker protein, LC3B ,to seletively activate the autophagic degradation of Caveolin-1, thereby reducing LDL transcytosis and slowing the development of diabetic AS. The research foundings will provide new strategies and methods for the prevention and treatment of diabetic AS.