KLF5 Exacerbates Myocardial Ischemia/Reperfusion Injury By Blocking Autophagic Flux

BackgroundKLF5,a krüppel-like transcription factor,plays an important role in the biological function of the body.Previous studies showed that KLF5 aggravated oxidative stress,apoptosis,myocardial hypertrophy and fibrosis.However,the role of KLF5 in myocardial ischemia/reperfusion(MIR)injury remains unclear.ObjectiveThe study aimed to determine the role of KLF5 in the regulation of autophagic flux and MIR injury.MethodsThe mechanism of KLF5 in myocardial ischemia/reperfusion injury was verified by the myocardial ischemia/reperfusion model in mice,hypoxia/reoxygenation-treated cardiomyocyte model and angiotensin II-treated fibroblast model.In order to downregulate the expression of KLF5,mouse heart was transfected by AAV2/9 virus through in situ injection,and the primary cardiomyocyte was transfected by siRNA.The autophagic inhibitor Bafilomycin A1 was used to block autophagic flux.The experimental study was performed using the following methods,such as Western blot,Tunel staining,the tandem fluorescence mRFP-GFP-LC3 analysis,Masson staining,TTC-Evans blue staining,echocardiography and transmission electron microscopy.ResultsFirst of all,we found that the expression of KLF5 was significantly increased in cardiomyocytes treated with hypoxia/reoxygenation and in mice during MIR.Then,downregulation of KLF5 reduced myocardial injury in mice with MIR,inhibited myocardial cell apoptosis and reduced ROS production in cardiomyocytes treated with hypoxia/reoxygenation.Further,we found that autophagic flux was impaired during MIR,whereas downregulation of KLF5 promoted autophagic flux in mice with MIR.Moreover,we used the autophagic inhibitor Bafilomycin A1 and found that downregulation of KLF5 inhibited myocardial cell apoptosis and attenuated mitochondrial damage in mice with MIR,whereas the protective effect of KLF5 was diminished with Bafilomycin A1.Finally,we observed whether downregulation of KLF5 had an effect on the cardiac function of mice with MIR for three weeks,and found that downregulation of KLF5 significantly improved the cardiac function of mice with MIR and suppressed cardiac fibrosis.ConclusionIn summary,we report here that KLF5 aggravates myocardial injury in mice with MIR by blocking autophagic flux,and clarify that KLF5 promotes cardiac dysfunction in mice with MIR for three weeks.