Gasdermin D mediates doxorubicin-induced cardiomyocyte pyroptosis and cardiotoxicity via directly binding to doxorubicin and changes in mitochondrial damage
Gasdermin D mediates doxorubicin-induced cardiomyocyte pyroptosis and cardiotoxicity via directly binding to doxorubicin and changes in mitochondrial damage
复制标题
Gasdermin D 通过直接与阿霉素结合以及线粒体损伤的变化介导阿霉素诱导的心肌细胞焦亡和心脏毒性
DOI：
10.1016/j.trsl.2022.05.001
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发表时间：
2022-08-26
影响因子：
7.8
通讯作者：
Han, Jibo
中科院分区：
文献类型：
--
作者：
Ye, Bozhi;Shi, Xiaowen;Han, Jibo
阿霉素（Doxorubicin, Dox）是一种广泛应用的蒽环类抗肿瘤药物，具有严重的心脏毒性。心肌细胞死亡和炎症参与了dox诱导的心脏毒性（DIC）的病理生理过程。Gasdermin D （GSDMD）被认为是焦亡的关键刽子手，焦亡是一种促炎程序化的细胞死亡。我们旨在研究GSDMD对DIC的影响，并系统地揭示其潜在机制。我们的研究结果表明，Dox通过siRNA或过表达质粒技术以gsdmd依赖的方式诱导心肌细胞焦亡。然后，我们通过CRISPR/Cas9系统生成GSDMD全球敲除小鼠，发现GSDMD缺乏减少了dox诱导的心肌病。Dox诱导炎性caspases的激活，随后间接介导GSDMD-N的生成。通过分子动力学模拟和无细胞系统，我们证实了Dox直接与GSDMD结合并促进GSDMD- n介导的焦亡。此外，GSDMD还通过Bnip3介导dox诱导的线粒体损伤和心肌细胞线粒体穿孔。这些发现为dox参与的GSDMD如何协调不良心脏毒性的机制提供了新的见解，并突出了GSDMD作为DIC潜在靶点的前景。（Translational Research 2022; 248:36-50）
Doxorubicin (Dox), as a widely used anthracycline antitumor drug, can cause severe cardiotoxicity. Cardiomyocyte death and inflammation are involved in the pathophysiology of Dox-induced cardiotoxicity (DIC). Gasdermin D (GSDMD) is known as a key executioner of pyroptosis, which is a pro-inflammatory pro-grammed cell death. We aimed to investigate the impact of GSDMD on DIC and systematically reveal its underlying mechanisms. Our findings indicated that Dox induced cardiomyocyte pyroptosis in a GSDMD-dependent manner by utilizing siRNA or overexpression-plasmid technique. We then generated GSDMD global knockout mice via CRISPR/Cas9 system and found that GSDMD deficiency reduced Dox-induced cardiomyopathy. Dox induced the activation of inflammatory cas-pases, which subsequently mediated GSDMD-N generation indirectly. Using molec-ular dynamics simulation and cell-free systems, we confirmed that Dox directly bound to GSDMD and facilitated GSDMD-N-mediated pyroptosis. Furthermore, GSDMD also mediated Dox-induced mitochondrial damage via Bnip3 and mito-chondrial perforation in cardiomyocytes. These findings provide fresh insights into the mechanism of how Dox-engaged GSDMD orchestrates adverse cardiotoxicity and highlight the prospects of GSDMD as a potential target for DIC. (Translational Research 2022; 248:36-50)