Abstract：
Endothelial cell dysfunction is the main pathology of atherosclerosis (AS). Sirtuin 6 (SIRT6), a deacetylase, is involved in AS progression. This study aimed to investigate the impacts of SIRT6 on the pyroptosis of endothelial cells and its underlying mechanisms. ApoE-/- mice were fed a high-fat diet (HFD) to establish the AS mouse model, atherosclerotic lesions were evaluated using oil red O staining, and blood lipids and inflammatory factors were measured using corresponding kits. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to establish the cell model, and pyroptosis was evaluated by flow cytometry, ELISA, and western blot. Immunoprecipitation (IP), co-IP, western blot, and immunofluorescence were used to detect the molecular mechanisms. The results showed that SIRT6 expression was downregulated in the blood of HFD-induced mice and ox-LDL-induced HUVECs. Overexpression of SIRT6 reduced atherosclerotic lesions, blood lipids, and inflammation in vivo and suppressed pyroptosis of HUVECs in vitro. Moreover, SIRT6 interacted with ASC to inhibit the acetylation of ASC, thus, reducing the interaction between ASC and NLRP3. Moreover, SIRT6 inhibits endothelial cell pyroptosis in the aortic roots of mice by deacetylating ASC. In conclusion, SIRT6 deacetylated ASC to inhibit its interaction with NLRP3 and then suppressed pyroptosis of endothelial cells, thus, decelerating the progression of AS. The findings provide new insights into the function of SIRT6 in AS.
摘要：
内皮细胞功能障碍是动脉粥样硬化（AS）的主要病理。Sirtuin6(SIRT6)，脱乙酰酶，参与AS进展。本研究旨在探讨SIRT6对内皮细胞焦亡的影响及其机制。ApoE-/-小鼠饲喂高脂饮食(HFD)建立AS小鼠模型,使用油红O染色评估动脉粥样硬化病变，使用相应的试剂盒测量血脂和炎症因子。用氧化低密度脂蛋白(ox-LDL)处理人脐静脉内皮细胞(HUVECs)建立细胞模型,通过流式细胞术评估焦亡，ELISA,和westernblot.免疫沉淀(IP),co-IP,westernblot,和免疫荧光检测的分子机制。结果显示SIRT6在HFD诱导的小鼠和ox-LDL诱导的HUVECs血液中表达下调。SIRT6的过表达减少了动脉粥样硬化病变，血脂,和体内炎症，体外抑制HUVECs的焦亡。此外，SIRT6与ASC相互作用以抑制ASC的乙酰化，因此，减少ASC和NLRP3之间的相互作用。此外，SIRT6通过脱乙酰ASC抑制小鼠主动脉根部的内皮细胞焦亡。总之,SIRT6去乙酰化ASC以抑制其与NLRP3的相互作用，然后抑制内皮细胞的焦亡，因此，减缓AS的进展。这些发现为SIRT6在AS中的功能提供了新的见解。
