GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis

Yuanyuan Wei, Beidi Lan, Tao Zheng, Lin Yang, Xiaoxia Zhang, Lele Cheng, Gulinigaer Tuerhongjiang, Zuyi Yuan () and Yue Wu ()
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Yuanyuan Wei: The First Affiliated Hospital of Xi’an Jiaotong University
Beidi Lan: The First Affiliated Hospital of Xi’an Jiaotong University
Tao Zheng: The First Affiliated Hospital of Xi’an Jiaotong University
Lin Yang: Xi’an Jiaotong University
Xiaoxia Zhang: Xi’an Jiaotong University
Lele Cheng: The First Affiliated Hospital of Xi’an Jiaotong University
Gulinigaer Tuerhongjiang: The First Affiliated Hospital of Xi’an Jiaotong University
Zuyi Yuan: The First Affiliated Hospital of Xi’an Jiaotong University
Yue Wu: The First Affiliated Hospital of Xi’an Jiaotong University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36614-w

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