Epigenetic State Changes Underlie Metabolic Switch in Mouse Post-Infarction Border Zone Cardiomyocytes

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Molecular Cardiology

Background:

• Myocardial infarction leads to ventricular muscle loss and scar formation.
• Surviving cardiomyocytes in the infarct border zone experience significant functional and structural changes.
• The epigenetic regulation of these border zone cardiomyocyte adaptations remains incompletely understood.

Purpose of the Study:

• To investigate the epigenetic mechanisms driving metabolic changes in cardiomyocytes after myocardial infarction.
• To identify specific genes and regulatory pathways affected in border zone cardiomyocytes.

Main Methods:

• Isolation and transcriptome analysis of cardiomyocyte nuclei from healthy and post-myocardial infarction mouse hearts.
• Chromatin immunoprecipitation followed by sequencing (ChIP-seq) for H3K27ac.
• Analysis of transcription factor binding motifs and gene expression changes.

Main Results:

• Border zone cardiomyocytes show downregulated fatty acid metabolism and oxidative phosphorylation genes, with modest induction of glycolysis genes (e.g., Glut1, Pfkp).
• Epigenetic profiling revealed a shift in chromatin association from Mef2 to AP-1 and enrichment of PPAR/RXR motifs at H3K27ac-reduced sites.
• Key PPAR target genes involved in metabolism (e.g., PGC-1α, Cpt2) were downregulated with associated epigenetic changes.

Conclusions:

• Epigenetic state changes and altered gene regulation are crucial for the metabolic switch observed in border zone cardiomyocytes post-myocardial infarction.
• The findings highlight the role of epigenetic modifications in adapting cardiomyocyte metabolism to ischemic injury.