Abstract 287: Metabolic Control of Ischemic Cardiac Injury in Human Cardiomyocytes

Abstract

Acute myocardial infarction is a leading cause of cardiac dysfunction and heart failure. As a result, developing in vitro models of myocardial ischemia has been important for the elucidation of the mechanisms of hypoxic injury and the development of novel cardioprotective strategies. During acute ischemia, cardiac injury occurs in minutes to hours in vivo but in hours to days in vitro. This difference in response to ischemia is compounded by differences in cardiomyocytes’ (CMs) metabolism and substrate utilization under standard in vitro growth conditions. An important challenge in modeling ischemia has been to faithfully recapitulate the in vivo cellular response to hypoxic stress. To address this limitation, we have performed comprehensive phenotypic characterization of myocardial metabolism and contractile functions in vitro during normoxia and hypoxia under different metabolic conditions. We show that, unlike CMs in the adult heart, adult murine CMs and hPSC-CMs cultured in glucose as the primary energy source utilize aerobic glycolysis and not oxidative phosphorylation (OXPHOS) for ATP generation. In contrast, CMs cultured with fatty acids as the primary energy source are dependent on OXPHOS for ATP generation and contractile function. Consistent with these findings, only CMs cultured in fatty acid have an acute drop in ATP production and contractility in response to hypoxia. We then show that by modulating the transcriptional activity of hypoxia-inducible factor 1-alpha, its upstream regulator sirtuin, and its downstream target lactate dehydrogenase A, CMs cultured in glucose shift their metabolism from glycolysis to the more metabolically appropriate OXPHOS. Collectively, our results provide novel mechanistic insights into the key regulatory pathways that control hPSC-CMs’ energy metabolism and highlight the significance of comprehensive characterization of CMs’ metabolic and functional responses to ischemic stress in vitro. By creating in vitro models of ischemic injury that can faithfully recapitulate cellular responses of myocardial infarction, it is then possible to identify relevant therapeutic targets for the treatment the disease.