Abstract 16115: Rapamycin Protects Diabetic Heart Against Ischemia-reperfusion Injury by Inhibiting JNK and STAT4
Background: Persistent activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and plays a critical role in myocardial injury following ischemia/reperfusion. Recently we reported that mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress and alteration of antioxidants and contractile protein expression. Since increased JNK and STAT4 activities have been strongly associated with T2D-induced cardiovascular complications, we hypothesized that rapamycin would reduce myocardial infarction (MI) in T2D mice through inhibition of JNK and STAT4.
Methods and Results: Adult male wild type (C57) or db/db T2D mice were treated daily for 28 days with rapamycin (0.25 mg/kg, i.p.). Following treatment, the hearts were subjected to global I (30 min) and R (60 min) in Langendorff mode. In addition, cardiomyocytes were isolated from treated mice and subjected to 40 min simulated ischemia (SI) and 1 hr or 18 hr reoxygenation (RO) to assess necrosis (by trypan blue staining) or apoptosis (by TUNEL assay), respectively. Diabetes exacerbated ischemic infarct size (measured by tetrazolium chloride staining) in db/db mice as compared to C57 mice (Fig. A), and also enhanced cardiomyocyte necrosis (Fig. B) and apoptosis (Fig. C). Rapamycin treatment reduced infarct size following I/R and protected adult cardiomyocytes against necrosis and apoptosis following SI/RO. Rapamycin also improved post-ischemic contractile function in db/db mice (Fig. D). Western blot analysis revealed a marked increase in phosphorylation of JNK and STAT4 in diabetic hearts, which were reduced in rapamycin-treated diabetic hearts (Fig. E).
Conclusion: Rapamycin treatment reduces MI possibly by inhibiting JNK and STAT4 in T2D heart. We propose that inhibition of JNK and STAT4 with rapamycin therapy may be an attractive strategy to improve prognosis in diabetics following MI.
Author Disclosures: F.N. Salloum: None. R.C. Kukreja: None. A. Das: None.
- © 2015 by American Heart Association, Inc.