The Development of Novel Acute Myocardial Infarction Therapeutics Using Metabolomics and High-Throughput Screening

University Of Rochester, Rochester NY

Investigators

Abstract

ABSTRACT Ischemia-reperfusion (IR) injury is the underlying pathology of acute myocardial infarction (AMI). Paradoxically, current AMI therapies have the common goal of promoting reperfusion and, in doing so, trigger events that lead to cell death. As a result, there is a need for new therapeutics that limit reperfusion-induced injury. Many of the pathologic cellular events of reperfusion-induced injury can be attributed to maladaptive metabolic remodeling. One particular metabolite of interest is succinate, which accumulates during ischemia. Upon reperfusion, succinate is consumed in the electron transport chain by Complex (Cx) II, generating reactive oxygen species at Cx I. This reverse electron transport (RET) appears to be a major contributor to IR injury, and recently prevention of ischemic succinate accumulation has been proposed as a novel cardioprotective strategy. Interestingly, ischemic succinate accumulation appears to be an evolutionarily conserved phenomenon, suggesting a potential role in hypoxic tolerance. These apparently contradictory observations led to the development of our central hypothesis: while succinate oxidation at reperfusion is detrimental to IR injury, succinate accumulation is beneficial for ischemic mitochondrial function. In our preliminary data, high-throughput screening identified nornicotine as a cardioprotective agent. Nornicotine improved post-IR cardiac function and reduced infarct size in a perfused heart model of IR injury. Nornicotine inhibited Cx I activity, and reduced succinate consumption at reperfusion, suggesting that inhibition of RET might be the mechanism of nornicotine-induced protection. Overall, this project will investigate an underexplored area of cardiac metabolism ? metabolic adaptations throughout ischemia ? and use these insights to develop novel AMI therapeutics.