Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.

Visker, J. R.; Cluntun, A. A.; Velasco-Silva, J. N.; Eberhardt, D. R.; Shankar, T. S.; Hamouche, R.; Ling, J.; Kwak, H.; Hillas, Y.; Aist, I.; Tseliou, E.; Navankasattusas, S.; Chaudhuri, D.; Ducker, G. S.; Drakos, S. G.; Rutter, J.

doi:10.1101/2024.02.01.577463

bioRxiv · 10.1101/2024.02.01.577463

Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.

Visker, J. R.·Cluntun, A. A.·Velasco-Silva, J. N.·Eberhardt, D. R.·Shankar, T. S.·Hamouche, R.·Ling, J.·Kwak, H.·Hillas, Y.·Aist, I.·Tseliou, E.·Navankasattusas, S.·Chaudhuri, D.·Ducker, G. S.·Drakos, S. G.·Rutter, J.

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Abstract

The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential ({Delta}{psi}), and Ca2+, increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/577463v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1a7a9b8org.highwire.dtl.DTLVardef@779e0aorg.highwire.dtl.DTLVardef@128d1f3org.highwire.dtl.DTLVardef@efc1bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Visker, J. R., Cluntun, A. A., Velasco-Silva, J. N., Eberhardt, D. R., Shankar, T. S., Hamouche, R., Ling, J., Kwak, H., Hillas, Y., Aist, I., Tseliou, E., Navankasattusas, S., Chaudhuri, D., Ducker, G. S., Drakos, S. G., Rutter, J.. 2024-02-04. Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.. https://doi.org/10.1101/2024.02.01.577463

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