沙库巴曲缬沙坦钠联合阿托伐他汀钙对糖尿病合并心力衰竭模型左心室重构通路的影响  

Effect of sacubactril valsartan sodium combined with atorvastatin calcium on left ventricular remodeling pathway in diabetic patients with heart failure

作　　者：栗小旭 杨静 任腾腾 LI Xiao-xu;YANG Jing;REN Teng-teng(Department of Pharmacy,the Third Hospital of Shandong Province,Jinan 250031,China;Department of Pharmacy,Shandong Medical College,Jinan 250031,China)

机构地区：[1]山东省立第三医院药学部,山东省济南市250031 [2]山东医学高等专科学校药学系

出　　处：《中国心血管病研究》2025年第1期58-63,共6页Chinese Journal of Cardiovascular Research

基　　金：山东省医药卫生科技发展计划项目(202213010928)。

摘　　要：目的探讨沙库巴曲缬沙坦钠与阿托伐他汀钙联合对糖尿病(DM)伴心力衰竭(HF)大鼠模型的心脏保护作用,并初步探讨可能的作用机制。方法2023年2月至11月,采用一次性腹腔注射50 mg/kg链脲佐菌素诱导DM模型,于DM大鼠中通过腹腔注射3 mg/kg阿霉素(每周1次,持续6周)诱导HF,将造模成功的40只大鼠随机分为模型组、诺欣妥组(10 mg/kg沙库巴曲缬沙坦钠灌胃)、美达信组(8.4 mg/kg阿托伐他汀钙灌胃)、联合组(10 mg/kg沙库巴曲缬沙坦钠和8.4 mg/kg阿托伐他汀钙灌胃),每组10只。另取10只大鼠作为对照组。采用超声心动图检查评估大鼠心功能[左心室射血分数(LVEF)、左心室短轴缩短率(LVFS)、左心室舒张末内径(LVEDD)、左心室收缩末期内径(LVESD)]。检测血清中心肌损伤标志物[肌酸激酶MB(CK-MB)、B型利钠肽(BNP)]水平。检测心肌组织中氧化应激[谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)]及炎症[白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)]相关标志物的水平。苏木精伊红染色、TUNEL染色、二氢乙锭(DHE)染色、免疫组织化学分析分别用于测定心肌组织病理损伤、心肌细胞凋亡、活性氧(ROS)水平和高迁移率族蛋白B1(HMGB1)阳性表达水平。采用蛋白免疫印迹分析HMGB1/Toll样受体(TLR)-4/核因子(NF)-κB通路相关蛋白的表达。结果与对照组相比,模型组LVEF[(34.06±2.08)%比(81.35±3.34)%]、LVFS[(20.03±1.17)%比(52.85±2.54)%]、GSH-Px[(0.84±0.16)μmol/L比(3.58±0.96)μmol/L]均明显降低,而LVEDD[(8.97±0.76)mm比(5.11±0.57)mm]、LVESD[(7.85±0.67)mm比(3.14±0.36)mm]、CK-MB[(28.26±2.74)ng/ml比(9.35±1.16)ng/ml]、BNP[(353.76±28.96)pg/ml比(220.15±15.75)pg/ml]、心肌细胞横截面积[(526.86±45.26)/μm2比(203.67±23.05)/μm2]、TUNEL阳性染色细胞比例[(46.62±2.02)%比(1.69±0.43)%]、ROS[(6.34±0.13)比(1.07±0.09)]、MDA[(30.37±2.21)nmol/L比(3.69±0.93)nmol/L]、IL-6[(34.59±2.25)μg/g protein比Objective To investigate the cardioprotective effects of sacubitril valsartan in combination with atovastatin calcium in a rat model of diabetes mellitus(DM)with heart failure(HF)and to preliminarily explore the possible mechanisms of the action.Methods From February 2023 to November 2023,DM model was induced by a one-time intraperitoneal injection of 50 mg/kg streptozotocin,and HF was induced by intraperitoneal injection of 3 mg/kg adriamycin(once a week for 6 weeks)in DM rats.40 rats with successful model construction were randomly divided into the model group,entresto group(10 mg/kg sacubitril valsartan by gavage),meidaxin group(8.4 mg/kg atovastatin calcium by gavage),and combined group(10 mg/kg sacubitril valsartan and 8.4 mg/kg atovastatin calcium gavage),10 in each group;another 10 rats were selected as the control group.Echocardiography was used to assess cardiac function[left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular end-diastolic diameter(LVEDD)and left ventricular end-systolic diameter(LVESD)].The levels of myocardial injury markers[creatine kinase MB(CK-MB)and brain natriuretic peptide(BNP)]in serum were detected.The levels of markers related to oxidative stress[glutathione peroxidase(GSH-Px)and malondialdehyde(MDA)]and inflammation[interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)]in myocardial tissue were detected.Hematoxylin eosin staining,TUNEL staining,dihydroethidium(DHE)staining and immunohistochemical analyses were used to determine myocardial tissue pathological injury,cardiomyocyte apoptosis,reactive oxygen species(ROS)levels and positive expression levels of high mobility group protein B1(HMGB1)respectively.Western blotting was used to analyze the expression of HMGB1/Toll-like receptor(TLR)-4/nuclear factor(NF)-κB pathway-related proteins.Results Compared with the control group,LVEF[(34.06±2.08)%vs.(81.35±3.34)%],LVFS[(20.03±1.17)%vs.(52.85±2.54)%]and GSH-Px[(0.84±0.16)μmol/L vs.(3.58±0.96)μmol/L]wer

关 键 词：糖尿病合并心力衰竭 沙库巴曲缬沙坦钠 阿托伐他汀钙 氧化应激 炎症反应 心功能 

分 类 号：Q95-33[生物学—动物学] R541.6[医药卫生—心血管疾病]