Abstract 19683: Reperfusion Therapy With Rapamycin Prevents Myocardial Injury by Induction of Cardiac MicroRNA-302a in Diabetic Rabbits
Background: Diabetes is a major risk factor for myocardial infarction (MI). Persistent activation of the mammalian target of rapamycin (mTOR) leads to diabetic complications and plays a critical role in myocardial reperfusion injury following MI. mTOR inhibition with rapamycin (RAPA) at reperfusion preserves cardiac function with reduction of myocardial infarction in type 2 diabetic mice. To demonstrate the clinical potential of these novel observations, we examined the effect of RAPA in a conscious diabetic rabbit model of MI and its associated molecular mechanism.
Methods and Results: To induce diabetes, alloxan monohydrate (125 mg/kg, i.v.) was administered in New Zealand white male rabbits (n=20; ∼ 3kg, 4 months old). Blood glucose level increased to 342±21 mg/dL following 2 weeks of alloxan administration. Balloon occluders were implanted and 7 days later, rabbits were subjected to 45-min ischemia (I) and 3 days of reperfusion (R). RAPA (0.25 mg/kg, i.v.) or DMSO (5% in saline, as vehicle) was infused 5 min before R. Plasma was collected at baseline, 1, 2, 4 and 24 hours during the procedure. RAPA significantly reduced MI in diabetic rabbits following I/R (Figure A) as assessed by triphenyltetrazolium chloride staining. RAPA also reduced cardiac troponin I level in blood at 1 hr and 2 hr of R as compared to vehicle alone (Figure B). RAPA significantly reduced apoptosis in the peri-infarct region (Figure C). Cardiac microRNA-302a, a regulator of anti-oxidative and anti-apoptosis through activating AKT signaling, was decreased after I/R in diabetic rabbits, but restored with RAPA treatment (Figure D). Moreover, RAPA inhibited diabetes-induced phosphorylation of S6, a marker of mTORC1 activation, but restored AKT in diabetic rabbit hearts (Figure E).
Conclusion: Rapamycin could be a promising drug in attenuation of reperfusion injury in diabetic subjects following acute MI by restoration of microRNA-302a and AKT signaling.
Author Disclosures: A. Samidurai: None. R.A. Ockaili: None. S.M. Filippone: None. C.K. Cain: None. J.F. Torrado: None. F.N. Salloum: None. R.C. Kukreja: None. A. Das: None.
- © 2016 by American Heart Association, Inc.