Peroxisome proliferator-activated receptor gamma (PPARG)-mediated myocardial salvage in acute myocardial infarction managed with left ventricular unloading and coronary reperfusion

Visker, J. R.; Tseliou, E.; Kyriakopoulos, C. P.; Hamouche, R.; Yin, M.; Ling, J.; Shankar, T.; Kwan, E.; Cedeno-Rosario, L.; Velasco-Silva, J.; Sideris, K.; Kwak, H.; Hillas, Y.; Yannias, E.; Maneta, E.; Srinivasan, H.; Padilla, L.; Polishchuck, G.; Navankasattusas, S.; Tandar, A.; Ducker, G.; Rutter, J.; Hong, T.; Shaw, R.; Lui, C.; Welt, F.; Drakos, S.

doi:10.1101/2025.02.11.637726

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bioRxiv · 10.1101/2025.02.11.637726

Peroxisome proliferator-activated receptor gamma (PPARG)-mediated myocardial salvage in acute myocardial infarction managed with left ventricular unloading and coronary reperfusion

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Abstract

Ischemic heart disease and acute myocardial infarction (AMI) is a leading cause of morbidity and mortality. Improvements have been made in coronary interventions to restore blood flow, but ischemia/reperfusion (I/R) injury significantly impacts clinical outcomes. We previously reported that activation of percutaneous mechanical unloading of the left ventricle (LV) with a transvalvular axial-flow device simultaneously with reperfusion improves myocardial salvage. However, the underlying mechanisms, potential adjuvant pharmacological interventions and the timing of the use of LV unloading as a cardioprotective approach in AMI are not well understood. This study investigated a) the mechanisms associated with improved myocardial salvage, b) a pharmacological intervention, and c) the timing of LV unloading. Following 90 minutes of ischemia, adult swine were subjected to reperfusion alone, simultaneous unloading with reperfusion, upfront unloading with delayed reperfusion, upfront reperfusion with delayed unloading, or reperfusion with concurrent use of esmolol and milrinone. Compared to controls, the simultaneous group had a 47% increase in myocardial salvage following AMI. This was associated with increased expression of neutrophil degranulation, macrophage activation, iNOS signaling, wound healing, and PPAR signaling. From these pathways, PPARG (peroxisome proliferator-activated receptor gamma) emerged as a potential cardioprotective gene that was uniquely overexpressed in the simultaneously unloaded and reperfused myocardium. Next, we showed PPARG agonism with rosiglitazone reduces mitochondrial oxygen demand in cardiomyocytes and in vivo, improves myocardial salvage following I/R injury in C57BL6/J mice. Thiazolidinediones (TZDs), such as rosiglitazone could be investigated as therapies combined with simultaneous LV unloading and coronary interventions to mitigate reperfusion injury. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/637726v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1c4d6e6org.highwire.dtl.DTLVardef@1f8d064org.highwire.dtl.DTLVardef@396eddorg.highwire.dtl.DTLVardef@9d932f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Visker, J. R., Tseliou, E., Kyriakopoulos, C. P., Hamouche, R., Yin, M., Ling, J., Shankar, T., Kwan, E., Cedeno-Rosario, L., Velasco-Silva, J., Sideris, K., Kwak, H., Hillas, Y., Yannias, E., Maneta, E., Srinivasan, H., Padilla, L., Polishchuck, G., Navankasattusas, S., Tandar, A., Ducker, G., Rutter, J., Hong, T., Shaw, R., Lui, C., Welt, F., Drakos, S.. 2025-02-15. Peroxisome proliferator-activated receptor gamma (PPARG)-mediated myocardial salvage in acute myocardial infarction managed with left ventricular unloading and coronary reperfusion. https://doi.org/10.1101/2025.02.11.637726

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