Abstract 16178: Role of LncRNA MALAT-1 and MicroRNA-199 in Rapamycin Induced Cardioprotection Against Reperfusion Injury in Diabetic Rabbits

Background:Treatment with rapamycin (RAPA, mTOR inhibitor) protects diabetic (DM) hearts against ischemia/reperfusion (I/R) injury. Coordination between MALAT-1 (Metastasis Associated Lung Adenocarcinoma Transcript 1, a long-noncoding RNA) and microRNA-199 (miR-199) plays an important role in cardiovascular diseases. However, the role of MALAT-1 dependent miR-199 regulation during myocardial infarction (MI) in diabetes is unknown.Methods and Results:Diabetes (blood glucose: 350?24 mg/dL) was induced by administration of alloxan monohydrate (125 mg/kg, i.v.) in New Zealand white rabbits (n=32; average 3kg, 4 month old). Myocardial I/R injury in conscious diabetic rabbit was performed by inflating previously (7 days prior to ischemia) implanted balloon occluder for 45 min. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before onset of reperfusion (3 or 10 days). RAPA treatment at reperfusion preserved post-MI ejection fraction (Fig. A). Post-I/R induction of apoptosis (evaluated by TUNEL staining after 3 days of reperfusion) was attenuated by RAPA treatment in DM hearts (Fig. B). Moreover, treatment with RAPA abolished the suppression of MALAT-1 expression in DM hearts following I/R injury (Fig. C). miRArray chip analysis revealed post-I/R induction of miR-199a-5p, a target of MALAT-1(Fig. D) in DM heart which was suppressed by RAPA (Fig. E). The anti-apoptotic protein Bcl-2, specific target of miR-199a-5p, was significantly down-regulated in heart of DM rabbit following I/R, which was restored upon RAPA treatment (Fig. F).Conclusion:Treatment with RAPA preserves MALAT-1, which potentially acts as sponge to suppress miR-199 and restores the expression of Bcl-2 in the diabetic heart following I/R injury. The MALAT-1-miR-199-Bcl-2 axis is a novel regulatory pathway that plays a critical role in preventing cell death in the diabetic myocardium following treatment with RAPA.