Abstract 17781: Reperfusion Therapy With Rapamycin Protects Type 2 Diabetic Mouse Heart
Background: Diabetic patients have an increased risk of heart failure and poor prognosis following myocardial infarction (MI). The persistent activation of mTOR (mammalian target of rapamycin) signaling contributes to the pathogenesis of diabetes and plays a critical role in myocardial reperfusion injury following ischemia. Since mTOR inhibition with rapamycin is protective against myocardial ischemia/reperfusion injury, we hypothesized that rapamycin treatment at reperfusion would reduce MI in type 2 diabetes.
Methods and Results: Hearts from adult male db/db or wild type (WT) C57 mice were subjected to 20 min stabilization, 30 min ischemia and 60 min reperfusion in Langendorff perfusion system. Hearts were infused with rapamycin (100 nM) or volume matched DMSO for first 20 min of reperfusion. Myocardial infarct size (TTC staining) was significantly reduced in rapamycin-treated db/db mice (13.3±2.4%) compared to DMSO-treated db/db (36.2±1.3%) or WT mice (27.7±1.1%)(p<0.001, n=3-6) (Fig. A). At the cellular level, ventricular cardiomyocytes were isolated from db/db and WT mice and subjected to 40 min of simulated ischemia (SI). At the onset of reoxygenation (RO), cardiomyocytes were treated with rapamycin (100 nM) or DMSO. Following 1 hr of RO, necrosis (trypan blue staining) and mitochondrial membrane potential (JC-1 staining) were measured. Apoptosis (TUNEL assay) and reactive oxygen species (ROS) (DCF staining) were determined following 18 hr RO. Rapamycin protected cardiomyocytes against necrosis (Fig. B) and apoptosis (Fig. C) after SI-RO compared to DMSO-treated cardiomycotes and also attenuated the loss of mitochondrial membrane potential (Fig. D) and generation of ROS (Fig. E).
Conclusion: Rapamycin treatment at reperfusion reduces MI by attenuating cardiomyocyte necrosis, apoptosis and ROS generation. We propose that reperfusion therapy with rapamycin may be an attractive strategy to improve prognosis in diabetics following MI.
- © 2013 by American Heart Association, Inc.