Study On The Effect And Mechanism Of Guanxinning Tablets On Heart Failure Mouse Model

Objective To observe the therapeutic effect of Guanxinning Tablets(GXNT)on heart failure(HF)mice,and further explore the protective mechanism of PI3K/AKT signaling pathway involved in GXNT on myocardial apoptosis in mice with heart failure,so as to provide experiment reference for the clinical application of GXNT.Methods Aortic arch constriction was performed in male ICR mice weighing 28-35 g.The mouse HF model was established.4 weeks after surgery,the survival mice were taken for echocardiography.44 mice were screened according to the ejection fraction(EF)and body weight,and divided into four groups,namely model,control groups(n=14),GXNT low dose group(GXNT,600 mg/kg)(n=10),GXNT high dose group(GXNT,1200 mg/kg)(n=10)and positive control group(Captopril,12.5 mg/kg)(n=10).Another 10 mice were selected as the sham operation group.Each drug-administered group was given the corresponding drug for 9 weeks,and the sham-operated group and the model control group were given 10 mL/kg of sterilized water.During the test,the general signs of the mice were observed,the survival rate was counted,and echocardiography was performed every 3 weeks to detect ventricular wall thickness and cardiac function.At the end of the administration,the levels of plasma NT-proBNP,AST,LDH,CK and CK-MB were measured.The myocardial tissue was taken for histopathological observation.The apoptosis of cardiomyocytes was observed by TUNEL staining,and the expression of BAX and BCL2 mRNA and PI3K,AKT,p-AKT,BCL2,and BAX protein were also detected.Results(1)At 9 weeks of administration,the survival rate of mice in the model control group,GXNT low-dose group and the high-dose group were 50%,60%and 70%,respectively.Compared with the sham operation group,the ventricular wall thickness,NT-proBNP,AST and CK levels in the model control group were significantly increased(P<0.01),while EF was markedly decreased(P<0.01).Pathological results showed that the myocardial fiber were swollen and disordered,inflammatory cells infiltrated in the myocardial interstitium,accompanied by significant myocardial fibrosis.Compared with the model control group,ventricular wall thickness in the GXNT high and low dose groups were significantly decreased at 3 weeks(P<0.05,P<0.01),and EF of the GXNT high dose group was markedly increased at 6 weeks(P<0.05),moreover,the EF of the GXNT high and low dose groups were increased significantly at 9 weeks(P<0.05,P<0.01).The levels of plasma NT-proBNP,AST and CK in the GXNT high and low dose groups were significantly decreased(P<0.05,P<0.01),and significantly reduced myocardial fibrosis and myocardial inflammatory cell infiltration,and improved myocardial cell pathological structure.(2)TUNEL-positive staining was not observed in the sham-operated group,and the model control group had more positive expression and a higher proportion of apoptotic cells.After the intervention of different doses of GXNT,the apoptosis was reduced to some extent.Compared with the sham-operation group,the relative expression of BAX mRNA in the myocardial tissue of the model control group was significantly increased(P<0.01),while BCL2 mRNA was decreased(P<0.01),and is consistent with the protein expression.The levels of PI3K and AKT phosphorylation were also significantly increased(P<0.05,P<0.01).Compared with the model control group,the expression levels of PI3K and p-AKT proteins as well as the expression BAX mRNA in myocardial tissue of GXNT high-dose group were significantly reduced(P<0.05).Conclusion GXNT can improve the survival rate of heart failure mice,reduce cardiac hypertrophy,enhance cardiac contraction and inhibit myocardial fibrosis.The roles may be related to the inhibition of activation of the PI3K/AKT/BAX signaling pathway to reduce cardiomyocyte apoptosis.