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.
Show 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
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Increased CPT1a expression is a critical cardioprotective response to pathological stress that suppresses gene programs for remodeling and enables rescue by gene transfer 97%
- Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart 96%
- The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction 96%
Similar papers in this journal
- AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism 97%
- SIRT2 inhibition protects against cardiac hypertrophy and heart failure 97%
- Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+ epicardium-derived cells. 97%
Similar papers in this journal
- Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control 96%
- Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity 96%
- Sodium-myo-inositol cotransporter-1, SMIT1, promotes cardiac hypertrophy and fibrosis induced by pressure overload in mice 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.