Abstract 117: Poly (i:c) Attenuates Myocardial I/R Injury via Glycolytic Dependent Yap Activation and by Suppression of MiR-143
Glycolytic metabolism plays a critical role in ischemia/reperfusion (I/R) injury. The Yes associated protein (YAP) is a core effector of the Hippo pathway that regulates cell proliferation and apoptosis. We observed that poly (I:C) enhanced glycolysis and Yap activation in neonatal cardiomyocytes. This study investigated whether poly (I:C) will attenuate myocardial I/R injury via a glycolytic dependent mechanism. 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. 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. The expression of miR-143 was markedly reduced and Yap levels were significantly increased in poly (I:C) treated hearts. In vitro data show that poly (I:C) treatment enhanced extracellular acidification rate (ECAR) and lactate production in HL-1 cardiomyocytes. In vivo inhibition of hexokinase 2 abolished poly (I:C)-induced cardioprotection. To determine the role of miR-143 in regulation of glycolysis, we transfected HL-1 cardiomyocytes with anti-miR-143 mimics before the cells were subjected to hypoxia/reoxygenation. We observed that anti-miR-143 significantly enhanced cell viability, reduced LDH release, and increased hexokinase 2 levels and extracellular acidification rate (ECAR). To determine whether suppression of miR-143 will induce protection against myocardial I/R injury, we loaded anti-miR-143 on 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. We conclude that poly (I:C) attenuates myocardial I/R injury via glycolytic dependent YAP mechanism and suppression of miR-143 expression.