Abstract 15702: Reperfusion Therapy With Rapamycin in Diabetic Heart: Essential Role of STAT3 Signaling
Background: Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and plays a critical role in myocardial reperfusion injury following ischemia. mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic (T2D) heart. Since activated STAT3 is decreased in T2D heart, we hypothesized that reperfusion therapy with rapamycin would reduce myocardial infarct size in these hearts through STAT3 signaling.
Methods and Results: Hearts from adult male db/db or wild type (WT) C57 mice were isolated and subjected to 30 min of ischemia and 60 min of reperfusion in Langendorff mode. Rapamycin (100 nM) was infused at the onset of reperfusion. Myocardial infarct size (IS) was significantly reduced in rapamycin-treated mice (13.3±2.4%) compared to DMSO control (36.2±1.3%) or WT mice (27.7±1.1%) (Fig. A). Rapamycin treatment restored phosphorylation of STAT3 and enhanced AKT phosphorylation (target of mTORC2), but significantly reduced ribosomal protein S6 phosphorylation (target of mTORC1) in heart (Fig. B). We further investigated the effect of rapamycin in high fat diet (HFD) fed inducible cardiac-specific STAT3-deficient (MCM TG:STAT3flox/flox) and WT mice (MCM TG:STAT3flox/flox). Rapamycin treatment during reperfusion significantly reduced IS in WT mice following I/R but not in STAT3-deficient mice (Fig. C). Rapamycin treatment during reoxygenation following 40 min of simulated ischemia also demonstrated resistance against necrosis (trypan blue staining) and apoptosis (TUNEL assay) in primary cardiomyocytes isolated from HFD-fed WT mice but not in cardiomyocytes from HFD-fed STAT3-deficient mice (Fig. D).
Conclusion: STAT3 signaling plays a critical role in reducing myocardial infarct size and attenuating cardiomyocyte death following reperfusion therapy with rapamycin in T2D.
Author Disclosures: A. Das: None. F.N. Salloum: None. D. Durrant: None. R.C. Kukreja: None.
- © 2014 by American Heart Association, Inc.