沙库巴曲缬沙坦对慢性心力衰竭模型小鼠心功能的影响及其作用机制  

Effect and Mechanism of Sacubitril Valsartan on Cardiac Function in Chronic Heart Failure Model Mice

作　　者：陈静静 吉秋霞 CHEN Jingjing;JI Qiuxia(Hai′an Hospital Affiliated to Nantong University,Nantong,Jiangsu,China 226600)

机构地区：[1]南通大学附属海安医院,江苏南通226600

出　　处：《中国药业》2024年第3期74-80,共7页China Pharmaceuticals

基　　金：2021年度江苏省南通市卫生健康委员会科研课题[QB2021028]。

摘　　要：目的探讨沙库巴曲缬沙坦对慢性心力衰竭(CHF)模型小鼠心功能的影响及其作用机制。方法通过主动脉缩窄术复制CHF模型小鼠,将40只建模成功的小鼠分为模型组(B组)、沙库巴曲缬沙坦组(C组)、沙库巴曲缬沙坦+EX-527组(D组)、沙库巴曲缬沙坦+Compound C组(E组),各10只;另取10只仅开胸未手术小鼠作为对照组(A组)。C组、D组、E组小鼠均灌胃68 mg/kg沙库巴曲缬沙坦(连续4周),D组和E组小鼠另分别腹腔注射1次5 mg/kg沉默信息调节因子2相关酶类1(Sirt1)抑制剂EX-527和20 mg/kg腺苷酸活化蛋白激酶(AMPK)抑制剂Compound C;A组和B组小鼠均分别灌胃、腹腔注射等量生理盐水。测定小鼠超声心动图指标左室射血分数(LVEF)、左室收缩末期内径(LVESd)、左室舒张末期内径(LVEDd);苏木精-伊红(HE)染色,观察小鼠的心肌组织病理形态;采用酶联免疫吸附试验(ELISA)检测小鼠血浆肌酸激酶MB型同工酶(CK-MB)、心肌肌钙蛋白Ⅰ(cTnⅠ)、白细胞介素6(IL-6)、肿瘤坏死因子-α(TNF-α)、超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-Px)水平;采用TUNEL法计数小鼠凋亡心肌细胞;采用实时荧光定量聚合酶链式反应(qRT-PCR)法和免疫印迹(Western blot)法测定小鼠心肌组织胱天蛋白酶3(caspase-3)、Sirt1、AMPK、过氧化物酶体增殖体激活受体γ辅助激活因子-1α(PGC-1α)mRNA和蛋白表达水平。结果与B组比较,C组小鼠心肌细胞变性、炎性细胞浸润程度减轻;LVEF,血浆SOD和GSH-Px水平,心肌组织Sirt1,AMPK,PGC-1αmRNA和蛋白表达水平均显著升高(P<0.05);LVEDd,LVESd,血浆CK-MB,cTnⅠ,IL-6,TNF-α,MDA水平,心肌细胞凋亡率,心肌组织caspase-3 mRNA和蛋白表达水平均显著降低(P<0.05)。与C组比较,D组、E组小鼠心肌损伤程度加重;LVEF,血浆SOD和GSH-Px水平,心肌组织Sirt1,AMPK,PGC-1αmRNA和蛋白表达水平均显著降低(P<0.05);LVEDd,LVESd,血浆CK-MB,cTnⅠ,IL-6,TNF-α,MDA水平,心肌细胞�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 troponinⅠ(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 infiltr

关 键 词：沙库巴曲缬沙坦 慢性心力衰竭 沉默信息调节因子2相关酶类1 腺苷酸活化蛋白激酶 过氧化物酶体增殖体激活受体γ辅助激活因子-1α 

分 类 号：R965[医药卫生—药理学] R972[医药卫生—药学]