Gasdermin D mediates doxorubicin- induced cardiomyocyte pyroptosis and cardiotoxicity via directly binding to doxorubicin and changes in mitochondrial damage

Transl Res. 2022 May 8:S1931-5244(22)00100-1. doi: 10.1016/j.trsl.2022.05.001. Online ahead of print.ABSTRACTDoxorubicin (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 programmed 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 caspases, which subsequently mediated GSDMD-N generation indirectly. Using molecular 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 mitochondrial 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.PMID:35545198 | DOI:10.1016/j.trsl.2022.05.001
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Source Type: research