The Mechanism Of Baicalein Regulate Oxidative Stress And Autophagy To Inhibit Cardiac Hypertrophy By Targeting FOXO3a

Objective Pathological hypertrophy refers to cardiac expansion in response to various unfavorable stimuli,such as myocardial ischemia,hypoxia,diabetes and hypertension.At present,there is no effective strategy for the treatment of cardiac hypertrophy,but some types of Traditional Chinese Medicine(TCM)might have cardio-protective effects,such as baicalein,curcumin and puerarin;however,it is important to clarify their molecular mechanisms.Baicalein is a natural flavonoid that exhibits cardioprotective properties because of excellent anti-oxidant and anti-inflammatory abilities,but its molecular mechanism in cardiac hypertrophy is still unclear.Therefore,it is meaningful to study the function and molecular mechanism of baicalein in cardiac hypertrophy.The purpose of this study is to explore the specific mechanism of baicalein in the treatment of myocardial hypertrophy and provide a new therapeutic strategy for myocardial hypertrophy.Methods(1)Isoproterenol(ISO)was used to construct a mouse model of cardiac hypertrophy.After treatment of baicalein,the indicators of cardiac hypertrophy were detected by echocardiography,histopathological examination,and real-time quantitative PCR analysis(RT-qPCR).(2)SD rat primary cardiomyocytes were used to verify the inhibitory effect of baicalein on cardiac hypertrophy by FRTC-conjugated phalloidin staining.(3)DCF fluorescence and Western blot were used to detect the therapeutic effects of baicalein on reactive oxygen species(ROS)outbreak and catalase inhibition induced by ISO.(4)Evaluation of baicalein on autophagy by LC3 double-labeled adenovirus transfection.(5)Molecular docking predicts baicalein targeting forkhead box protein subfamily O3(Foxo3a)(6)Chromatin immunoprecipitation assay(CHIP)and dual luciferase reporter genes assay were used to verify that Foxo3 a directly trans activated FUNDC1.Results(1)Baicalein treatment significantly inhibited cardiac hypertrophy in cells and animal models of cardiac hypertrophy induced by ISO.(2)Baicalein significantly inhibited the ROS burst and restored the level of catalase which induced by ISO.(3)Baicalein activated impaired autophagy.Western blot showed that the inhibitory effect of baicalein on cardiac hypertrophy was offset after autophagy was inhibited by autophagy inhibitors.(4)Foxo3a is likely to be a direct downstream target of baicalein.(5)Forced expression of Foxo3 a relieved the ROS brust,promoted the expression of catalase and promoted autophagy.(6)Mitochondrial autophagy protein FUNDC1 was the direct target of Foxo3 a.(7)Forced expression of FUNDC1 relieved ISO-induced cardiac hypertrophy.Conclusion We discovered a new molecular mechanism of baicalein’s effect on ISO-induced myocardial hypertrophy.Our data indicated that baicalein reduced ISO-induced myocardial hypertrophy by promoting the transcriptional activity of FOXO3 a.The transcriptional activity of FOXO3 a includes activation of the antioxidant gene Catalase to inhibit ROS burst,and activation of the autophagy-related gene FUNDC1 to activate damaged autophagy.This new molecular mechanism clarifies the therapeutic effect of baicalein on caridac hypertrophy,which might become a new potential therapeutic method with relatively minor side effects and significant effects,providing a new therapeutic strategy for myocardial hypertrophy.