The Role And Mechanism Of LRRC8A In Myocardial Ischemia/reperfusion Injury

Introduction:Myocardial ischemia-reperfusion injury(I/R)is a huge challenge in the treatment of acute myocardial infarction.At present,there is a lack of effective treatment for I/R.Previous studies have shown that VRAC could participate in myocardial I/R injury and cell autophagy,and LRRC8A is an important component of VRAC.In the present study,we investigate the role and mechanism of LRRC8A in myocardial I/R injury.Methods:In vivo experiment:we explored the role of LRRC8A in a mouse model of myocardial I/R injury with molecular biological approaches.In vitro experiment:we explored the effects of LRRC8A on apoptosis and autophagy induced by hypoxia-reoxygenation,and identified related signaling pathway by Western Blot,flow cytometry and cell fluorescence.Results:The expression of LRRC8A is reduced in myocardial I/R model.In vitro,overexpression of LRRC8A could reduce cardiomyocyte apoptosis induced by hypoxia-reoxygenation(H/R).Knockdown of LRRC8A increased the cardiomyocyte autophagy,while overexpression of LRRC8A leads to decrease in autophagy.Overexpression of LRRC8A promotes the number of autolysosomes and decrease autophagosomes to restore the impaired autophagy flux of myocardial cells.LRRC8A reduces the level of autophagy during H/R by inhibiting AMPK phosphorylation.Conclusions:LRRC8A plays a protective role in cardiomyocyte apoptosis and autophagy by restoring damaged autophagy flux and inhibiting AMPK phosphorylation.LRRC8A May be a new target to protect cardiomyocytes from I/R injury.