Study On The Effect And Mechanism Of Canagliflozin On Chronic Heart Failure Mice

Purpose: This study investigated the effect and mechanism of sodium glucose transporter(SGLT2 receptor inhibitors)—canagliflozin on chronic heart failure mice.Method: C57 mice were used as the background to establish a chronic heart failure mouse model.Real-time fluorescence quantitative PCR assay and Western blot assay were used to verify the establishment of chronic heart failure mouse model.In animal experiments,the effects of canagliflozin on mice with chronic heart failure were evaluated by real-time fluorescence quantitative PCR,Western blot,comparison of the ratio of heart to body weight,comparison of the gross view of the heart,IHC staining,WGA staining and CD31 staining of the heart tissue,and then tissue samples were sent for RNA sequencing.And the sequencing results were verified for speculating the mechanism of canagliflozin in mice with chronic heart failure.In cell experiments,PE was firstly used to induce hypertrophy of primary cardiomyocytes and increase of heart failure indexes,and then canagliflozin was used to treat and knock down the expression level of YAP/TAZ m RNA,so as to verify that canagliflozin can play a role in improving heart failure through the Hippo pathway.Result: In animal experiments,canagliflozin can reduce the expression levels of heart failure markers A natriuretic peptide(ANP)and B natriuretic peptide(BNP)in mouse with chronic heart failure.The ratio of heart weight to body weight of mouse showed that canagliflozin can reduce the ratio of heart to body weight of mouse with chronic heart failure.Westernblot and IHC experiment display canagliflozin can reduce the level of cardiac stress fibrosis in mice with chronic heart failure.Heart tissue WGA dyeing display canagliflozin can inhibit the cardiomyocytes hypertrophy.And heart tissue CD31 staining display canagliflozin can increase capillary density of the heart on the mouse with chronic heart failure.RNA sequencing of heart tissue suggested that Hippo pathway is one of the key molecular mechanisms of the effect of canagliflozin on mice with chronic heart failure,and Westernblot analysis of animal heart tissue further demonstrated the effect of canagliflozin on mice with chronic heart failure through the Hippo pathway.In cell experiments,PE induced increased expression of ANP and BNP,markers of heart failure,and hypertrophy of primary cardiomyocytes.Canagliflozin can reduce the expression levels of PE-induced ANP and BNP,and the m RNA levels of the downstream genes of YAP/TAZ,ANKRD1,CYR61 and β-MHC,as well as inhibit cardiomyocyte hypertrophy.Finally,knocking down the expression level of YAP/TAZ m RNA can inhibit PE-induced ANP expression.Conclusion: Canagliflozin plays a preventive and therapeutic role in mice with chronic heart failure by acting on cardiomyocytes,and its mechanism is related to Hippo pathway to a certain extent.