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Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling

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Abstract

Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) and decreased activation of STAT3 are implicated in diabetic complications. Considering the potent cardioprotective effect of mTOR inhibitor, rapamycin, we hypothesized that reperfusion therapy with rapamycin would reduce infarct size in the diabetic hearts through STAT3 signaling. Hearts from adult male db/db or wild type (WT) C57 mice were isolated and subjected to 30 min of normothermic global 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 vehicle control (35.9 ± 0.9 %) or WT mice (27.7 ± 1.1 %). Rapamycin treatment restored phosphorylation of STAT3 and enhanced AKT phosphorylation (target of mTORC2), but significantly reduced ribosomal protein S6 phosphorylation (target of mTORC1) in the diabetic heart. To determine the cause and effect relationship of STAT3 in cardioprotection, inducible cardiac-specific STAT3-deficient (MCM TG:STAT3flox/flox) and WT mice (MCM TG:STAT3flox/flox) were made diabetic by feeding high fat diet (HFD). Rapamycin given at reperfusion reduced IS in WT mice but not in STAT3-deficient mice following I/R. Moreover, cardiomyocytes isolated from HFD-fed WT mice showed resistance against necrosis (trypan blue staining) and apoptosis (TUNEL assay) when treated with rapamycin during reoxygenation following simulated ischemia. Such protection was absent in cardiomyocytes from HFD-fed STAT3-deficient mice. STAT3 signaling plays critical role in reducing IS and attenuates cardiomyocyte death following reperfusion therapy with rapamycin in diabetic heart.

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Acknowledgments

This work was supported by grants from the National Institutes of Health R37 HL051045, R01 HL079424, R01 HL093685, and R01 HL118808 (RCK), the American Heart Association 10SDG3770011 and 14GRNT20010003 (FNS), and A. D. Williams’ Fund of Virginia Commonwealth University Grant UL1RR031990 (AD).

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Authors and Affiliations

  1. Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA

    Anindita Das, Fadi N. Salloum, Scott M. Filippone, David E. Durrant & Rakesh C. Kukreja

  2. Institute of Molecular Cardiology, University of Louisville, Louisville, KY, 40292, USA

    Gregg Rokosh & Roberto Bolli

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  1. Anindita Das
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  2. Fadi N. Salloum
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  7. Rakesh C. Kukreja
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Correspondence to Anindita Das.

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Das, A., Salloum, F.N., Filippone, S.M. et al. Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling. Basic Res Cardiol 110, 31 (2015). https://doi.org/10.1007/s00395-015-0486-5

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