Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury

The clinical therapy for treating of acute myocardial infarctions are primary percutaneous coronary interventions (PPCI). PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt cardiac hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the injured heart. We deployed a pharmacological strategy of MCT4 inhibition usingVB124 at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential, and Ca2+, increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R. Our data suggest normalizing pyruvate-lactate metabolism via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury.