Abstract
In this study, we set out to identify an interlinked metabolic and epigenetic network that produces acetyl-CoA for histone acetylation and gene regulation, and determine whether this network promotes heart repair and protection after I/R injury. Myocardial ischemic reperfusion (I/R) injury induces dramatic metabolic changes and is accompanied with extensive epigenetic changes. Recent studies reveal that energy metabolism and chromatin epigenetics are intimately linked in cellular functions. In particular, acetyl-CoA is a building block for energy metabolism and histone acetylation. However, the acetyl-CoA mediated regulatory machinery integrating metabolic pathways and chromatin modifications has been under-explored in heart repair and protection. We conducted a screen of energy metabolites in promoting histone acetylation and heart repair both in vivo and in vitro. Our screen identified that acetate, pyruvate, and octanoic acid (8C) but not citrate and nonanoic acid (9C) improved heart function after MI in rats. In particular, 8C administration resulted in the most significant heart functional recovery after MI. More importantly, in a more clinically relevant setting, 8C injection at the time of reperfusion 45 minutes after left anterior descending coronary (LAD) ligation showed comparable repair effect to that of 8C administration before LAD ligation, suggesting that 8C could be a very effective metabolic natural product to treat MI. Mechanistically, 8C promoted histone acetylation in CM chromatin after IR injury and inhibited CM death by activating expression of anti-oxidant genes Nrf2, HO1, and NQO1. We further established that the 8C promoted histone acetylation and heart repair was transduced by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetylase GCN5/KAT2A. Therefore, this study has elucidated an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and KAT2A in stimulating histone acetylation and anti-oxidative stress gene expression to combat heart injury. This study provides a novel strategy for treating myocardial I/R disease at the interface of metabolism and epigenetics.
Published Version
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