Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Zhejiang, China (J.H., X.S., B.H., J.X.).
The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency (S.D.), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Hypertension. 2022 Nov;79(11):2505-2518. doi: 10.1161/HYPERTENSIONAHA.122.20004. Epub 2022 Sep 6.
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.
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.
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.
心肌肥厚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，血管紧张素 II（Ang II）或压力超负荷会导致心肌细胞和心肌组织中 GSDMD（gasdermin D）的激活。然而，GSDMD 对心肌肥厚的直接影响及其潜在机制尚不完全清楚。
在本研究中，我们研究了 GSDMD 在小鼠和人类肥厚心肌中的异常激活，结果表明 GSDMD 缺乏可减少 Ang II 或压力超负荷诱导的小鼠心肌肥厚、功能障碍和相关的心肌细胞细胞焦亡。在体内和体外，机制上，Ang II 介导的 GSDMD 切割导致 STING（干扰素基因刺激物）激活的线粒体功能障碍。反过来，STING 的激活增强了 GSDMD 介导的心肌肥厚。此外，GSDMD 和 STING 的缺乏均可抑制心脏特异性 GSDMD 过表达小鼠的心肌肥厚。
基于这些发现，我们提出了一种机制，即 GSDMD 与线粒体-STING 轴一起产生自我放大的正反馈环。这一发现表明 GSDMD 有望成为与肥厚相关的心脏病的关键治疗靶点。
