Epigenetic silencing of FCGR2A by promoter hypermethylation exacerbates cardiac remodeling in post-myocardial infarction heart failure

Post-myocardial infarction heart failure (post-MI HF) is among the cardiovascular diseases with the highest morbidity and mortality rates worldwide. However, the epigenetic landscape of post-MI HF remains incompletely characterized. Here reduced representation bisulfite sequencing and RNA sequencing were performed on left ventricular tissues from a rat model of post-MI HF. Candidate genes were validated in human ischemic cardiomyopathy datasets. Integrated analysis identified FCGR2A as a top candidate, exhibiting promoter hypermethylation accompanied by transcriptional downregulation in failing hearts. This finding was conserved in human ischemic cardiomyopathy. FCGR2A downregulation exacerbated, whereas its overexpression attenuated, ischemia-hypoxia-induced cardiomyocyte apoptosis and intracellular calcium overload. Mechanistically, FCGR2A downregulation enhanced L-type calcium channel current density, thereby promoting calcium overload and activating the mitochondrial apoptotic pathway. Furthermore, ATF3 was identified as an upstream transcriptional repressor that binds to the FCGR2A promoter and facilitates its hypermethylation. The detrimental effects of ATF3 overexpression were rescued by restoration of FCGR2A expression. Our study delineates a novel ATF3/FCGR2A axis in post-MI HF, in which ATF3-driven promoter hypermethylation silences FCGR2A, leading to calcium dysregulation and cardiomyocyte apoptosis. FCGR2A represents a potential diagnostic biomarker and therapeutic target for preventing adverse cardiac remodeling.