Effect Of Trehalose On Myocardial Hypertrophy And The Underlying Mechanisms

Background:Heart failure is the terminal stage of many heart diseases,there are still high rates of prevalence,mortality,and hospitalization.The treatment of heart failure is a clinical challenge and has become the focus of current research.A variety of factors such as hemodynamic changes,inflammation,autophagy,apoptosis,mitochondrial damage,endothelial dysfunction and other factors lead to changes in the internal environment of the heart,resulting in cardiac remodeling.Pathological changes such as abnormal myocardial hypertrophy and reactive myocardial fibrosis can be alleviated by regulating these factors.This is the key strategy for the prevention and treatment of heart failure.Therefore,this study focuses on elucidating the underlying mechanisms of myocardial hypertrophy and finding pharmacological interventions that target these molecular changes.Objective:This study aimed to evaluate the effect and mechanism of trehalose on myocardial hypertrophy,and further demonstrate the role of autophagy in myocardial hypertrophy,explore the potential of trehalose as an anti-myocardial hypertrophy drug,and explore its possibility for the treatment of pathological myocardial hypertrophy and heart failure.Methods:The mouse cardiac hypertrophy model was established by transverse aortic constriction(TAC),and the cardiomyocyte hypertrophy model was induced by angiotensin II.The effect of trehalose in vivo was evaluated by cardiac ultrasound,histopathological section staining,western blot,and the effect of trehalose in vitro was evaluated by q PCR,immunofluorescence,Western Blot.The role of autophagy in myocardial hypertrophy was evaluated by western blot,adenovirus transfection.TFEB was inhibited by transfection of si RNA to explore whether trehalose plays a role in myocardial hypertrophy by regulating TFEB.Transcriptome sequencing was used to reveal the potential mechanism of trehalose in myocardial hypertrophy.Results:This study found that the trehalose can significantly attenuate TAC-induced cardiac hypertrophy and Ang II-induced cardiomyocyte hypertrophy.In vivo,trehalose significantly improved cardiac dysfunction,myocardial fibrosis and cardiomyocyte size which induced by TAC.In vitro,trehalose significantly reduced the expression of cardiac hypertrophy-related proteins.Moreover,LC3 II and P62 expressions were both increased in pathological myocardial hypertrophy in mice,suggesting that autophagy was inhibited.In vitro,angiotensin II-stimulated cardiomyocytes showed inhibited autophagy flux,while trehalose could improve the above situation.Trehalose significantly activated TFEB and increased its nuclear translocation.Transfection of si RNA TFEB reduced the expression of TFEB in cardiomyocytes,and the improvement of trehalose in cardiomyocyte hypertrophy was inhibited.Using transcriptome sequencing technology,54 genes were found to be down-regulated and 214 genes were up-regulated after trehalose treatment compared with TAC group.The key target genes were found by co-analysis with the differentially expressed genes in the TAC postoperative group.Among them,9 up-regulated genes were found,including Ifi27l2 b,Ccl5,Eldr,Sertm1,Clec2 l,1110035H17Rik,Plin1,S100a9,and Zfp957(Tcf20),and 3 down-regulated genes,namely Faddos,Rag1 and Pld5.Conclusion:Trehalose can alleviate pathological myocardial hypertrophy by regulating TFEB and promoting autophagy.In addition,the potential targets of trehalose in cardiac hypertrophy were discovered by transcriptome sequencing,which may be related to immunity and apoptosis.Therefore,this study suggests that trehalose may be a potential therapeutic drug for the treatment of pathological cardiac hypertrophy and heart failure.