The Role And Mechanism Of Adar1 In Apoptosis Of Cardiomyocytes After Myocardial Infarction

Background:Myocardial infarction(MI)is the most severe complication of coronary heart disease,which is a significant cause of death from cardiovascular disease in the world.Massive loss of cardiomyocytes contributes to cardiac dysfunction,of which apoptosis is the main molecular basis.Double-stranded RNA-specific adenosine deaminase,Adar1,is a ubiquitously expressed enzyme that deaminates adenosine to inosine(A-to-I)of target RNA to regulate the development and apoptosis of embryonic heart.However,the role of Adar1 in myocardial infarction remains unknown.This study aims to explore the role and molecular mechanism of Adar1 in myocardial infarction.Methods:We directly injected adenovirus carrying Adar1 sh RNA in the infarcted area,or intraperitoneally injected Adar1 inhibitors in the mouse model of myocardial infarction,to explore the effect of Adar1 on cardiomyocyte apoptosis and cardiac function.Meanwhile,we applied hypoxia treatment in the isolated neonatal mouse cardiomyocytes in vitro to measure Adar1 expression.Then loss of function assay was used to explore the molecular mechanism of Adar1 on cardiomyocyte apoptosis.Result:The expression of Adar1 was significantly increased after myocardial infarction,which peaked at 3 days post-MI.Through the separation of cardiomyocytes and non-cardiomyocytes in adult myocardial tissue after myocardial infarction,a significant increase was observed in Adar1 expression in cardiomyocytes at 3 days and in non-cardiomyocytes at 7 days after myocardial infarction.By injecting adenovirus carrying Adar1-sh RNA into the infarcted area of myocardium,we found that Adar1 knockdown significantly increased cell apoptosis and exacerbated cardiac dysfunction.Meanwhile,inhibition of Adar1,through injecting Adar1 inhibitors intraperitoneally,impaired the cardiac function after myocardial infarction.Furthermore,knockdown of Adar1 promoted hypoxia-induced apoptosis in primary cardiomyocytes.Mechanistically,we have found that Adar1 regulated cardiomyocyte apoptosis mainly through mitochondrial-related apoptosis.Furthermore,IFIT2 may play an important role in the mitochondria-associated apoptotic pathway regulated by Adar1.Conclusion:Increased Adar1 expression in myocardial tissue early after myocardial infarction may have cardioprotective effects,and Adar1 knockdown or inhibition promotes cell apoptosis and deterioration of cardiac function.The mitochondrial damage induced by Adar1 deficiency is the main molecular mechanism of cell apoptosis.