Department of Cardiovascular Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Clin Exp Hypertens. 2023 Dec 31;45(1):2189138. doi: 10.1080/10641963.2023.2189138.
Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload.
Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA.
We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway.
In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload.
Gasdermin D（GSDMD）形成膜孔以执行细胞焦亡。但是，心肌细胞焦亡如何引起压力超负荷导致的心脏重构的机制尚不清楚。我们研究了 GSDMD 介导的细胞焦亡在压力超负荷导致的心脏重构发病机制中的作用。
野生型（WT）和心肌细胞特异性 GSDMD 缺陷型（GSDMD-CKO）小鼠接受横主动脉缩窄（TAC）以诱导压力超负荷。手术后 4 周，通过超声心动图、侵入性血流动力学和组织学分析评估左心室结构和功能。通过组织化学、RT-PCR 和 Western blot 研究与细胞焦亡、肥大和纤维化相关的相关信号通路。通过 ELISA 测量来自健康志愿者或高血压患者的血清 GSDMD 和 IL-18 水平。
我们发现 TAC 诱导心肌细胞细胞焦亡和促炎细胞因子 IL-18 的释放。高血压患者的血清 GSDMD 水平明显高于健康志愿者，并且诱导成熟的 IL-18 释放更为剧烈。GSDMD 缺失显著减轻 TAC 诱导的心肌细胞细胞焦亡。此外，心肌细胞中 GSDMD 的缺失显著减少心肌肥大和纤维化。GSDMD 介导的细胞焦亡导致心脏重构的恶化与激活 JNK 和 p38 信号通路有关，但与 ERK 或 Akt 信号通路无关。
总之，我们的结果表明 GSDMD 是压力超负荷诱导的心脏重构中细胞焦亡的关键执行者。GSDMD 介导的细胞焦亡激活 JNK 和 p38 信号通路，这可能为压力超负荷诱导的心脏重构提供新的治疗靶点。
