Sirtuin 6 可使凋亡相关斑点样蛋白 (ASC) 去乙酰化,从而抑制动脉粥样硬化中的内皮细胞猝死现象

IF 1.2 4区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS International heart journal Pub Date : 2024-05-15 DOI:10.1536/ihj.23-334
Jian Huang, Shuilin Dong, Yanhui Wu, Huiming Yi, Wei Zhang, Xi Ai
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引用次数: 0

摘要

内皮细胞功能障碍是动脉粥样硬化(AS)的主要病理现象。Sirtuin 6(SIRT6)是一种去乙酰化酶,参与了动脉粥样硬化的进展。本研究旨在探讨 SIRT6 对内皮细胞热解的影响及其内在机制。用高脂饮食(HFD)喂养载脂蛋白E-/-小鼠建立强直性脊柱炎小鼠模型,用油红O染色法评估动脉粥样硬化病变,用相应的试剂盒测定血脂和炎症因子。用氧化低密度脂蛋白(ox-LDL)处理人脐静脉内皮细胞(HUVECs)以建立细胞模型,并用流式细胞术、ELISA和Western印迹法评估热蛋白沉积。免疫沉淀(IP)、共沉淀(co-IP)、Western 印迹和免疫荧光用于检测分子机制。结果表明,SIRT6在HFD诱导的小鼠血液和氧化-LDL诱导的HUVECs中表达下调。过表达 SIRT6 可减少体内动脉粥样硬化病变、血脂和炎症,抑制体外 HUVECs 的热凋亡。此外,SIRT6 与 ASC 相互作用,抑制了 ASC 的乙酰化,从而减少了 ASC 与 NLRP3 之间的相互作用。此外,SIRT6 还能通过去乙酰化 ASC 来抑制小鼠主动脉根部内皮细胞的脓毒症。总之,SIRT6通过使ASC去乙酰化来抑制其与NLRP3的相互作用,进而抑制内皮细胞的热凋亡,从而减缓强直性脊柱炎的进展。这些发现为SIRT6在强直性脊柱炎中的功能提供了新的见解。
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Sirtuin 6 Deacetylates Apoptosis-Associated Speck-Like Protein (ASC) to Inhibit Endothelial Cell Pyroptosis in Atherosclerosis

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.

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来源期刊
International heart journal
International heart journal 医学-心血管系统
CiteScore
2.50
自引率
6.70%
发文量
148
审稿时长
6-12 weeks
期刊介绍: Authors of research articles should disclose at the time of submission any financial arrangement they may have with a company whose product figures prominently in the submitted manuscript or with a company making a competing product. Such information will be held in confidence while the paper is under review and will not influence the editorial decision, but if the article is accepted for publication, the editors will usually discuss with the authors the manner in which such information is to be communicated to the reader.
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