Loss of DNA methyltransferase 3a enhances Caspase-8 transcription and promotes cardiomyocyte pyroptosis during myocardial infarction.

Aspartate-specific cysteine protease (Caspase)-8 plays a critical role in initiating pyroptosis by mediating cleavage and activation of gasdermin-D (Gsdmd) during Yersinia infection. However, the role of Caspase-8 in pyroptosis after myocardial infarction (MI) and its underlying mechanism remains elusive. Here we show that Caspase-8 is essential for cardiomyocyte pyroptosis post MI and Caspase-8/Gsdmd signaling pathway is activated in hearts of male infarcted mice. The inhibition of Caspase-8 in male mice rescues the decline of cardiac function and cardiomyocyte pyroptosis following MI. Dnmt3a is further shown to impact DNA methylation on the CpG island of Caspase-8 promoter and regulate Caspase-8 expression. Dnmt3a overexpression protects myocardium from MI in male mice by inhibiting cardiomyocyte pyroptosis. Moreover, reduction of Dnmt3a in MI is attributed to the increased ubiquitination. Our study identifies a regulatory axis, Dnmt3a/Caspase-8/Gsdmd, which drives ischemic heart injury by promoting cardiomyocyte pyroptosis, and suggests potential therapeutic targets for heart diseases.