GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis
GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis
复制标题
GSDMD (Gasdermin D) 介导病理性心脏肥大并通过线粒体-STING（干扰素基因刺激器）轴产生前馈放大级联
DOI：
10.1161/hypertensionaha.122.20004
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发表时间：
2022-11-01
期刊：
影响因子：
8.3
通讯作者：
Ye, Bozhi
中科院分区：
文献类型：
--
作者：
Han, Jibo;Dai, Shanshan;Ye, Bozhi
背景：心肌肥大最初是心肌细胞对神经体液或血流动力学刺激的适应性反应。有证据表明，Ang II（血管紧张素II）或压力超负荷导致心肌细胞和心肌组织中GSDMD（gasdermin D）激活。然而，GSDMD对心肌肥厚的直接影响及其潜在机制尚未完全了解。方法与结果：在这项研究中，我们研究了GSDMD在小鼠和人类肥大心肌中的异常激活，结果表明，GSDMD缺乏减少了小鼠Ang II或压力超负荷诱导的心脏肥大，功能障碍和相关的心肌细胞焦亡。从机制上讲，血管紧张素II介导的GSDMD切割导致线粒体功能障碍上游的STING（刺激因子干扰素基因）激活在体内和体外。STING的激活反过来增强GSDMD介导的心脏肥大。此外，缺乏GSDMD和STING抑制心脏特异性GSDMD过表达小鼠的心脏肥大。结论：基于这些发现，我们提出了一种机制，GSDMD产生一个自放大，积极的前馈回路与ESTA STING轴。这一发现指出了GSDMD作为肥大相关心脏病的关键治疗靶点的前景。
Background: Cardiac hypertrophy is initially an adaptive response of cardiomyocytes to neurohumoral or hemodynamic stimuli. Evidence indicates that Ang II (angiotensin II) or pressure overload causes GSDMD (gasdermin D) activation in cardiomyocytes and myocardial tissues. However, the direct impact of GSDMD on cardiac hypertrophy and its underlying mechanisms are not fully understood. Methods and Results: In this study, we examined the aberrant activation of GSDMD in mouse and human hypertrophic myocardia, and the results showed that GSDMD deficiency reduced Ang II or pressure overload–induced cardiac hypertrophy, dysfunction, and associated cardiomyocyte pyroptosis in mice. Mechanistically, Ang II–mediated GSDMD cleavage caused mitochondrial dysfunction upstream of STING (stimulator of interferon genes) activation in vivo and in vitro. Activation of STING, in turn, potentiated GSDMD-mediated cardiac hypertrophy. Moreover, deficiency of both GSDMD and STING suppressed cardiac hypertrophy in cardiac-specific GSDMD-overexpressing mice. Conclusions: Based on these findings, we propose a mechanism by which GSDMD generates a self-amplifying, positive feed-forward loop with the mitochondria-STING axis. This finding points to the prospects of GSDMD as a key therapeutic target for hypertrophy-associated heart diseases.