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Reperfusion Therapy with Rapamycin Prevents Myocardial Injury and restores Plasma Levels of Stress‐Sensitive microRNA‐191 in Conscious Diabetic Rabbits
Author(s) -
Samidurai Arun,
Ockaili Ramzi,
Kukreja Rakesh C,
Das Anindita
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1278.5
Subject(s) - medicine , alloxan , myocardial infarction , pi3k/akt/mtor pathway , diabetes mellitus , ischemia , cardiology , reperfusion injury , troponin i , anesthesia , endocrinology , pharmacology , apoptosis , chemistry , biochemistry
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 ischemia. mTOR inhibition with rapamycin 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 rapamycin in a conscious diabetic rabbit model of MI. In addition we examined whether rapamycin influences the plasma levels of stress‐sensitive microRNA‐191. Methods and Results To induce diabetes, alloxan monohydrate (125 mg/kg, i.v.) was administered in New Zealand white rabbits (n=10; average 3kg, 4 month old). Blood glucose levels increased to 345±66 mg/dL (n=10) following 2 weeks of alloxan administration. Subsequently, balloon occluders were implanted and 7 days later, these rabbits were subjected to a 30‐min ischemia and 3 days of reperfusion. Rapamycin (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before reperfusion. Plasma was collected at baseline, 1, 2, 4 and 24 hours during the procedure. The results show that rapamycin significantly reduced myocardial infarction in diabetic rabbit following I/R ( Figure 1A) as assessed by triphenyltetrazolium chloride staining. Rapamycin also reduced cardiac troponin I level in blood at 1 hr and 2 hr of reperfusion as compared to vehicle alone ( Figure 1B). Moreover the plasma levels of microRNA‐191 were decreased at 1 and 2 hr after I/R which were significantly elevated with rapamycin treatment. Conclusion The current translational study suggests that rapamycin could be a promising drug in attenuation of reperfusion injury in diabetic patients following acute MI. Also, micro‐RNA‐191 may have a role in attenuation of I/R injury following rapamycin treatment. Support or Funding Information NIH R37 HL051045, RO1 HL079424, RO1 HL093685, RO1 HL118808 (RCK) A.D. Williams’ Fund of VCU UL1RR031990 (AD) VCU National Center for Advancing Translational Sciences (UL1TR000058) and CCTR Endowment Fund (AD)