Abstract
Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.
Highlights
44 Energy is a fundamental requirement for all living organisms and its production typically requires fuels and oxygen
Our results suggested that 8C-produced acetyl-CoA contributed to epigenetic regulation of antioxidant genes in response to ischemia reperfusion (I/R) injury. 241 medium-chain acyl-CoA dehydrogenase (MCAD) was required for the conversion of 8C into acetyl-CoA and subsequent histone acetylation increase and heart protection 244 To ascertain whether 8C produced acetyl-CoA contributed tothe rescue of histone acetylation after simulated ischemia reperfusion (sI/R), we knocked down MCAD (Figure 5-figure supplement 1A), a key enzyme in the generation of acetyl-CoA from 8C28
Our study further reveals that 8C-stimulated histone acetylation leads 306 to increase of antioxidant gene expression for heart repair
Summary
Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. How energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. We examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. We elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury. Our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury. 40 41
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