Protective Mechanism Of Sirt3 On Post-infarction Cardiac Injury

Background and Objective:Mitochondrial damage is involved in the pathogenesis of post-infarction cardiac injury.However,the upstream regulators of mitochondrial damage have not yet been identified.The aim of our study is to explore the role of Sirt3 in post-infarction cardiac injury with a particular focus on mitochondrial fission.Methods:Wild type and Sirt3 transgenic mice were selected as experimental subjects to establish in vivo and vitro model of heart injury after myocardial infarction.Western blot,TUNEL staining,ELISA,Masson staining,qPCR,echocardiography,myocardial cell function detection,immunofluorescence,cell flow cytometry and JC-1 staining were used to evaluate the degree of myocardial injury,mitochondrial structure and function damage and the expression of related signaling pathway proteins in post-myocardial infarction model.loss-and gain-of-function assays were used to identify the role of mitochondrial fission and AMPK pathways in Sirt3 attenuating post-infarction cardiac injury.Results:Sirt3 was downregulated in the progression of post-infarction cardiac injury.Overexpression of Sirt3 attenuated cardiac fibrosis,sustained myocardial function,inhibited the inflammatory response,and reduced cardiomyocyte death.Functional studies illustrated that chronic post-infarction cardiac injury was characterized by increased mitochondrial fission,which triggered mitochondrial oxidative stress,metabolic disorders,mitochondrial potential reduction and caspase9 apoptosis in cardiomyocytes.However,Sirt3 overexpression attenuated mitochondrial fission and thus preserved mitochondrial homeostasis and cardiomyocyte viability.Furthermore,our results confirmed that Sirt3 repressed mitochondrial fission via normalizing AMPK-Drpl pathways.Inhibition of AMPK activity re-activated Drpl and thus abrogated the inhibitory effect of Sirt3 on mitochondrial fission.Conclusion:Sirt3 inhibits the phosphorylation of Drpl by phosphorylation of AMPK,thus inhibiting the excessive mitochondrial division and maintaining mitochondrial function,to ameliorate the cardiac injury after myocardial infarction.