Abstract 13498: Reperfusion Therapy With Rapamycin Prevents Myocardial Ischemic Injury, Through Activation of AKT and ERK

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Background: The selective inhibitor of mammalian target of rapamycin (mTOR), rapamycin (RAPA), has been shown to exert preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. Two distinct mTOR complexes (mTORC1 and mTORC2) differentially regulate cardiomyocyte apoptosis and tissue damage following myocardial infarction. We hypothesized that reperfusion therapy with RAPA would reduce myocardial infarct size through differential modulation of mTOR complexes and MAP kinases. Methods and Results: Adult C57BL mice were subjected to 30 min of ischemia via left anterior descending coronary artery ligation followed by reperfusion for 24 hr. RAPA (0.25 mg/kg) or 10% DMSO (volume-matched control) was administered via intra-cardiac injection at the onset of reperfusion. Post I/R survival (90%) and cardiac function (fractional shortening, FS: 26.9±2.6%) were improved in RAPA-treated mice compared to control (survival: 60%, FS:16.7±3.2%). Additionally, RAPA caused significant reduction in myocardial infarct size (Fig. 1A), measured by tetrazolium chloride staining, and apoptosis (Fig. 1B) in peri-infarct regions, assessed by TUNEL staining. Western blot analysis revealed that RAPA restored Akt473 phosphorylation (target of mTORC2), but reduced ribosomal protein S6 phosphorylation (target of mTORC1) following I/R injury (Fig. 1C). The protective effect of RAPA was associated with increased phosphorylation of ERK1/2 and decreased phosphorylation of P38 (Fig. 1D). RAPA also attenuated pro-apoptotic protein Bax, in concert with increased pro-survival Bcl2 to Bax ratio (Fig. 1E). Conclusion: Reperfusion therapy with RAPA protects hearts against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTOC1 and P38. We propose that RAPA could be a novel treatment strategy to modulate mTOR complexes and MAP kinase signaling for attenuation of reperfusion injury in the heart.