Abstract
Myocardial infarction causes ventricular muscle loss and formation of scar tissue. The surviving myocardium in the border zone, located adjacent to the infarct, undergoes profound changes in function, structure and composition. How and to what extent these changes of border zone cardiomyocytes are regulated epigenetically is not fully understood. Here, we obtained transcriptomes of PCM-1-sorted mouse cardiomyocyte nuclei of healthy left ventricle and 7 days post myocardial infarction border zone tissue. We validated previously observed downregulation of genes involved in fatty acid metabolism, oxidative phosphorylation and mitochondrial function in border zone-derived cardiomyocytes, and observed a modest induction of genes involved in glycolysis, including Slc2a1 (Glut1) and Pfkp. To gain insight into the underlying epigenetic regulatory mechanisms, we performed H3K27ac profiling of healthy and border zone cardiomyocyte nuclei. We confirmed the switch from Mef2- to AP-1 chromatin association in border zone cardiomyocytes, and observed, in addition, an enrichment of PPAR/RXR binding motifs in the sites with reduced H3K27ac signal. We detected downregulation and accompanying epigenetic state changes at several key PPAR target genes including Ppargc1a (PGC-1α), Cpt2, Ech1, Fabpc3 and Vldrl in border zone cardiomyocytes. These data indicate that changes in epigenetic state and gene regulation underlie the maintained metabolic switch in border zone cardiomyocytes.
Highlights
Introduction iationsMyocardial infarction (MI) remains one of the leading causes of mortality [1]
border zone (BZ) Cardiomyocytes Downregulate Genes Involved in Lipid Metabolism
To compare the transcriptomes of cardiomyocyte nuclei between cardiomyocytes from the BZ and the healthy left ventricle (LV), myocardial infarction was induced by ligation of the left descending coronary artery on 8-week-old male mice
Summary
Introduction iationsMyocardial infarction (MI) remains one of the leading causes of mortality [1]. The oxygen shortage suppresses oxidative fatty acid (FA) metabolism and activates anaerobic glycolysis to reduce the consumption of the limited oxygen [2]. This acute phase is followed by death of irreplaceable cardiomyocytes and other cells in the ischemic region, immune responses and scar formation [3]. The infarct zone (IZ) is highly irregular in shape, consisting of necrotic tissue, infiltrating fibroblasts and immune cells, which will subsequently give rise to fibrous tissue. Cardiomyocytes of the border zone (BZ) surrounding the IZ are still viable, but severely affected by the ischemia, infiltrating immune cells and fibroblasts of the neighboring infarct zone [4].
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