Loss of MEF2A in myocardial cells exacerbates cardiomyocyte senescence following myocardial infarction by modulating the COX family
Stress-induced cell senescence plays a crucial role in maintaining cardiac function after AMI, but the specific mechanism remains unclear. The objective of this study was to investigate the regulatory role of myocyte enhancer factor 2A (MEF2A) in cardiomyocyte senescence and its impact on cardiac function following AMI. Cardiomyocyte-specific MEF2A knockout mice (MEF2A-MyH6-CreErt2(f/f,+)) were generated, and their anterior descending branches were ligated to establish an AMI model. Ultrasound assessment of cardiac function 30 days post-AMI revealed that the specific knockout of MEF2A in cardiomyocytes worsened cardiac dysfunction and fibrosis, increased biomarkers of myocardial necrosis, and led to senescence in cardiomyocytes. Through high-throughput sequencing analysis of mRNA and protein in myocardial tissue from both MEF2A-MyH6-Creert2 (f/f,+) and wild-type mice, it was discovered that there was a decrease in expression levels for the enzymes of the cyclooxygenase (COX) family after MEF2A knockout. Additionally, KEGG analysis showed that differentially expressed genes were linked to cellular senescence processes . This suggests that MEF2A plays a regulatory role in cellular senescence through its interaction with the cox family. Meanwhile, COX inhibitors were found to weaken the beneficial effects of MEF2A overexpression on cardiomyocyte senescence in H9C2 cells. Our observations showed that knocking out MEF2A led to a decrease in H3K4me3 methylation levels and an increase in H3K4me3 antibody binding to specific cox family promoters when overexpressed. The use of MM102, a methylation inhibitor, nearly eliminated the positive effects of MEF2A overexpression on cell senescence, providing evidence that regulation of methylation is how MEF2A influences COX family expression changes. After screening, it was found that MEF2A can affect the methyltransferase activity partly by regulating the transcription level of SET1A subunit. Overall design: Chromatin immunoprecipitation DNA-sequencing(Chip-seq) for histone H3K4me3 in H9C2 cells with  MEF2A overexpression and control.