Nature Communications ( IF 14.7 ) Pub Date : 2023-02-18 , DOI: 10.1038/s41467-023-36614-w Yuanyuan Wei 1 , Beidi Lan 1, 2 , Tao Zheng 1, 2 , Lin Yang 3 , Xiaoxia Zhang 4 , Lele Cheng 1, 2 , Gulinigaer Tuerhongjiang 1, 2 , Zuyi Yuan 1, 2 , Yue Wu 1, 2
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Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME−/−/ApoE−/− mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.
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GSDME 介导的细胞焦亡促进动脉粥样硬化的进展和相关炎症
细胞焦亡是一种 Gasdermin 介导的细胞死亡,会加剧炎症。为了验证 GSDME 介导的细胞焦亡加剧动脉粥样硬化进展的假设,我们生成了ApoE和GSDME双缺陷小鼠。与对照小鼠相比,GSDME -/- /ApoE -/-小鼠在高脂饮食诱导下表现出动脉粥样硬化病变区域和炎症反应的减少。人动脉粥样硬化单细胞转录组分析表明GSDME主要在巨噬细胞中表达。在体外,氧化低密度脂蛋白 (ox-LDL) 诱导巨噬细胞中的 GSDME 表达和细胞焦亡。从机制上讲, GSDME的消融在巨噬细胞中抑制 ox-LDL 诱导的炎症和巨噬细胞焦亡。此外,信号转导和转录激活因子 3 (STAT3) 与 GSDME 表达直接相关并正向调节。本研究探讨了GSDME在动脉粥样硬化发展过程中的转录机制,并表明 GSDME 介导的动脉粥样硬化进展过程中的细胞焦亡可能是动脉粥样硬化的潜在治疗方法。