Abstract 20607: Suppression of MiR-143 By Poly I:C Attenuates Myocardial I/r Injury Involving Glycolytic Dependent Yap Activation

Introduction: We observed that Toll like receptor 3 (TLR3) is required for the neonatal heart repair and regeneration after myocardial ischemic injury and TLR3 ligand, Poly (I:C) enhances glycolysis and Yap activation in neonatal cardiomyocytes. Hypothesis: Poly (I:C) will attenuate I/R-induced myocardial injury via a glycolytic dependent activation of YAP mechanism. Methods: Mice (n=6/group) were treated with Poly (I:C) (10 μg/25g body weight) one h before the hearts were subjected to ischemia (45 min) followed by reperfusion (24 h). Sham surgery served as sham control. Results: Poly (I:C) treatment significantly reduced infarct size by 35% and enhanced EF% by 20.5% and FS% by 24.9% compared with I/R group. Poly I:C administration significantly decreased the levels of miR-143 and increased Yap expression in the myocardium. In vitro data showed that Poly (I:C) enhanced extracellular acidification rate (ECAR) and lactate production in HL-1 cardiomyocytes. In vivo inhibition of glycolytic metabolism abolished Poly (I:C)-induced cardioprotection. To investigate whether miR-143 will regulate glycolysis, we transfected HL-1 cardiac myocytes with anti-miR-143 mimics before the cells were subjected to hypoxia/reoxygenation. The data showed that anti-miR-143 significantly enhanced cell viability, reduced LDH release, and increased ECAR. To determine whether suppression of miR-143 will induce a cardioprotection against myocardial I/R injury, we loaded anti-miR-143 on bone marrow derived exosomes (Exo-antimiR-143) by transection of bone marrow stromal cells with anti-miR-143 mimics. MiR-control mimics served as control (Exo-miR-control). Exo-miR-143 was delivered into the myocardium through the right carotid artery immediately before the hearts (n=6/group) were subjected to I/R. We observed that delivery of Exo-antimiR-143 significantly enhanced EF% by 20.5% and FS% by 26.4% and decreased infarct size by 42.2%, when compared with untreated I/R group. Delivery of Exo-miR-control did not alter I/R-induced cardiac dysfunction and infarct size. Conclusions: Poly (I:C) attenuates myocardial I/R injury via suppression of miR-143, leading to enhanced glycolysis and YAP expression.