Effect and Mechanism of Sacubitril Valsartan on Cardiac Function in Chronic Heart Failure Model Mice
Objective To investigate the effect and mechanism of sacubitril valsartan on cardiac function in chronic heart failure(CHF)model mice.Methods CHF model mice were replicated through aortic constriction surgery.Forty successfully modeled mice were divided into the model group(group B),sacubitril valsartan group(group C),sacubitril valsartan + EX-527 group(group D),and sacubitril valsartan + Compound group C(group E),with 10 mice in each group;another 10 mice without surgery were selected as the control group(group A).Mice in groups C,D,and E were orally administered 68 mg/kg of sacubitril valsartan(for four weeks).Additionally,mice in groups D and E were intraperitoneally injected with 5 mg/kg of silent mating type information regulation 2 homolog 1(Sirt1)inhibitor EX-527 and 20 mg/kg of adenosine monophosphate-activated protein kinase(AMPK)inhibitor Compound C,respectively.Mice in groups A and B mice were given an equal volume of normal saline by gavage and intraperiton eal injection,respectively.The echocardiography indicators such as left ventricular ejection fraction(LVEF),left ventricular end-systolic diameter(LVESd),and left ventricular end-diastolic diameter(LVEDd)of mice were measured.Hematoxylin-eosin(HE)staining was used to observe the histopathological morphology of myocardium.Enzyme-linked immunosorbent assay(ELISA)was used to detect the levels of plasma creatine kinase MB type isoenzyme(CK-MB),cardiac troponin Ⅰ(cTnⅠ),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),superoxide dismutase(SOD),malondialdehyde(MDA),and glutathione peroxidase(GSH-Px).TUNEL method was used to determine the apoptosis of cardiomyocytes.Real-time fluorescence quantitative polymerase chain reaction(qRT-PCR)and Western blot were used to determine the expression levels of caspase-3,Sirt1,AMPK,and peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α)mRNA and protein in myocardial tissue of mice.Results Compared with those in group B,the degree of myocardial cell degeneration and inflammatory cell infiltration in group C reduced,the levels of LVEF,plasma SOD and GSH-Px,and the expression levels myocardial tissue Sirt1,AMPK,PGC-1α mRNA and protein in group C significantly increased(P<0.05),while the LVEDd,LVESd,the levels of plasma CK-MB,cTnⅠ,IL-6,TNF-α and MDA,the myocardial cell apoptosis rate,and the expression levels of caspase-3 mRNA and protein in the myocardium in group C significantly reduced(P<0.05).Compared with those in group C,the degree of myocardial injury in group D and group E increased,the levels of LVEF,plasma SOD and GSH-Px,and the expression levels of myocardial tissue Sirt1,AMPK,PGC-1α mRNA and protein in group D and group E significantly reduced(P<0.05),while the LVEDd,LVESd,the levels of plasma CK-MB,cTnⅠ,IL-6,TNF-α and MDA,the myocardial cell apoptosis rate,and the expression levels of caspase-3 mRNA and protein in the myocardium in group D and group E significantly increased(P<0.05).Conclusion Sacubitril valsartan may affect the cardiac function of CHF model mice by activating Sirt1/AMPK/PGC-1α signaling pathway.
万方数据
维普
