Department of Cardiovascular Medicine, Cangzhou Central Hospital, Cangzhou, Hebei 061001, P.R. China.
Department of Cardiovascular Medicine, Hebei Province Cangzhou Hospital of Integrated Traditional and Western, Cangzhou, Hebei 061001, P.R. China.
Mol Med Rep. 2022 Feb;25(2). doi: 10.3892/mmr.2021.12556. Epub 2021 Dec 8.
Interferon regulatory factor (IRF) 2 is a transcription factor belonging to the IRF family, which is essential for gasdermin D (GSDMD)‑induced pyroptosis. Decreasing myocardial cell pyroptosis confers protection against heart damage and cardiac dysfunction caused by myocardial infarction (MI). The aim of the present study was to investigate the involvement of IRF2 in MI and the underlying mechanism of IRF2 in pyroptosis. To mimic MI, ligation of the left anterior descending coronary artery was performed to establish an mouse model and rat cardiomyocytes H9c2 cells were cultured under hypoxic conditions to establish an model. Transthoracic echocardiography was used to assess cardiac function. Hematoxylin and eosin staining was used to observe histopathological changes in the myocardial tissue. Immunohistochemistry and western blotting were performed to detect IRF2 expression levels. TUNEL staining and flow cytometry were used to detect apoptosis in myocardial tissue and cells. Chromatin immunoprecipitation and dual luciferase reporter assay were used to verify the effect of IRF2 on GSDMD transcription. IRF2 was upregulated in MI mice. MI induced pyroptosis, as evidenced by increased GSDMD, N‑terminal GSDMD (GSDMD‑N), and cleaved (c‑) caspase‑1 levels. MI increased IL‑1β and IL‑18 levels. These alterations were alleviated by IRF2 silencing. Furthermore, in hypoxia‑treated H9c2 cells, IRF2 silencing significantly decreased the elevated levels of IL‑1β and IL‑18 and pyroptosis‑associated proteins, including GSDMD, GSDMD‑N and c‑caspase1. Moreover, in hypoxia‑treated H9c2 cells, IRF2 directly bound to the GSDMD promoter to drive GSDMD transcription and promote pyroptosis and IRF2 expression may be regulated via the hypoxia inducible factor 1 signaling pathway. In conclusion, the present results demonstrated that IRF2 is a key regulator of MI by mediating pyroptosis, which triggers GSDMD activation.
干扰素调节因子 (IRF) 2 是一种转录因子，属于 IRF 家族，对于 Gasdermin D (GSDMD) 诱导的细胞焦亡至关重要。减少心肌细胞焦亡可防止心肌梗死 (MI) 引起的心脏损伤和心功能障碍。本研究旨在探讨 IRF2 在 MI 中的作用及其在细胞焦亡中的作用机制。通过结扎左前降支冠状动脉建立 小鼠模型模拟 MI，培养缺氧条件下的大鼠心肌细胞 H9c2 细胞建立 模型。通过经胸超声心动图评估心功能。苏木精-伊红染色观察心肌组织的组织学变化。免疫组化和 Western blot 检测 IRF2 表达水平。TUNEL 染色和流式细胞术检测心肌组织和细胞的凋亡。染色质免疫沉淀和双荧光素酶报告基因检测用于验证 IRF2 对 GSDMD 转录的影响。IRF2 在 MI 小鼠中上调。MI 诱导焦亡，表现为 GSDMD、N 端 GSDMD (GSDMD-N) 和裂解的 caspase-1 水平增加。MI 增加了 IL-1β 和 IL-18 水平。IRF2 沉默减轻了这些改变。此外，在缺氧处理的 H9c2 细胞中，IRF2 沉默显著降低了升高的 IL-1β 和 IL-18 以及与细胞焦亡相关的蛋白，包括 GSDMD、GSDMD-N 和 c-caspase1 的水平。此外，在缺氧处理的 H9c2 细胞中，IRF2 直接与 GSDMD 启动子结合，驱动 GSDMD 转录，促进细胞焦亡，IRF2 表达可能通过缺氧诱导因子 1 信号通路调节。综上所述，本研究结果表明，IRF2 通过介导引发 GSDMD 激活的细胞焦亡，成为 MI 的关键调节因子。
