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. Herein we reported Caspase-8 is essential for cardiomyocyte pyroptosis post MI and Caspase-8/GSDMD signaling pathway is obviously activated in the infarcted hearts. The inhibition of Caspase-8 rescued the decline of cardiac function, myocardium injury and cardiomyocyte pyroptosis in MI mice. Conversely, forced expression of Caspase-8 aggravated cardiac injury in mice. Cardiomyocyte-specific knockout of GSDMD blunted the damage effects of Caspase-8 overexpression on cardiac function in mice. Bisulfite Sequencing PCR (BSP) analysis of infarcted hearts showed a CpG island with significantly reduced methylation levels near the Caspase-8 transcription start site (TSS). Methylated modification of this locus was mediated by DNMT3a, and negatively regulated Caspase-8 expression. In vivo, overexpression of DNMT3a alleviated cardiac function decline and cardiomyocyte pyroptosis by suppressing Caspase-8 in MI mice. Furthermore, the reduction of DNMT3a during MI was attributed to the increased ubiquitination. Demethylation of this locus obtained more opportunity of transcription factor (TF) binding like as HES1. Our study uncovers a novel regulatory axis, DNMT3a/Caspase-8/GSDMD, which drives post-MI cardiac injury by promoting cardiomyocyte pyroptosis, and suggested new therapeutic targets for ischemic heart diseases.