附萸汤通过调控Nrf2/GPX4介导的铁死亡对心力衰竭大鼠心肌纤维化的影响  

Fuyu Decoction ameliorates myocardial fibrosis in rat model of heart failure by regulating Nrf2/GPX4-mediated ferroptosis

作　　者：王青青 张莉芬[1] 马金苗 黄静[1] 王毅[1] 孝玲玲 顼志兵[1] WANG Qing-qing;ZHANG Li-fen;MA Jin-miao;HUANG Jing;WANG Yi;XIAO Ling-ling;XU Zhi-bing(Emergency Department of the Seventh People′s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai 200137,China)

机构地区：[1]上海中医药大学附属第七人民医院急诊科,上海200137

出　　处：《中国中药杂志》2024年第3期789-797,共9页China Journal of Chinese Materia Medica

基　　金：上海市卫生健康委员会中医药科研项目(2022QN020);上海中医药大学附属第七人民医院中医继承人项目(JCR2023-04)。

摘　　要：探究附萸汤(Fuyu Decoction,FYD)对心力衰竭(heart failure,HF)大鼠心肌纤维化的作用及机制。将60只Wistar大鼠分为造模组50只和假手术组(sham)10只。采用结扎大鼠左冠状动脉前降支构建心肌梗死后HF模型。将建模成功大鼠分为模型组(model)、FYD低剂量组(FYD-L)、FYD高剂量组(FYD-H)、FYD+Nrf2抑制剂组(FYD+ML385),每组各10只。FYD-L和FYD-H大鼠分别给予2.5、5.0 g·kg^(-1)FYD灌胃,FYD+ML385大鼠给予5.0 g·kg^(-1)的FYD灌胃同时腹腔注射30 mg·kg^(-1)的ML385,sham和model大鼠给予等量生理盐水灌胃。各组大鼠干预8周后,检测心功能指标,观察心肌组织形态结构和胶原沉积,检测心肌组织collagenⅠ、collagenⅢ蛋白阳性表达、细胞凋亡、氧化应激、二价亚铁离子(Fe^(2+))和活性氧(reactive oxygen species,ROS)水平,检测心肌组织核因子E2相关因子2(nuclear factor-erythroid 2-related factor 2,Nrf2)、溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)、酰基辅酶A合成酶长链家族成员4(recombinant acyl coenzyme A synthetase long chain family,member 4,ACSL4)蛋白表达。与sham组相比,model组大鼠左室射血分数(left ventricular ejection fraction,LVEF)、左室短轴缩窄率(left ventricular fractional shortening,LVFS)显著降低,左室收缩末期内径(left ventricular end systolic diameter,LVIDs)、左室舒张末期内径(left ventricular end diastolic diameter,LVIDd)显著升高,心肌胶原沉积增多,且collagenⅠ、collagenⅢ蛋白阳性表达,细胞凋亡率,丙二醛(malondialdehyde,MDA),Fe^(2+),ROS水平均显著升高,超氧化物歧化酶(superoxide dismutase,SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH)水平以及Nrf2、SLC7A11和GPX4蛋白表达均显著降低,ACSL4蛋白表达显著升高。与model相比,FYD各剂量组大鼠上述指标均得到显著改善。与FYD-H组相比,ML385能够显著逆转FYD对HF大鼠心肌纤维化的保�This study aims to investigate the effect and mechanism of Fuyu Decoction(FYD)in the treatment of myocardial fibrosis in the rat model of heart failure(HF).Sixty Wistar rats were randomized into a modeling group(n=50)and a sham group(n=10).A post-myocardial infarction HF model was established by ligating the left anterior descending coronary artery in rats.The successfully modeled rats were assigned into model,low-dose(2.5 g·kg^(-1))FYD(FYD-L),high-dose(5.0 g·kg^(-1))FYD(FYD-H),and FYD+Nrf2 inhibitor(ML385,30 mg·kg^(-1))groups(n=10).FYD was administrated by gavage and ML385 by intraperitoneal injection.The rats in the sham and model groups were administrated with equal amounts of normal saline by gavage.After 8 weeks of intervention,the cardiac function indicators were measured,and the myocardial tissue morphology and collagen deposition were observed.The positive expression of collagensⅠandⅢ,apoptosis,and oxidative stress were examined,and the levels of Fe^(2+)and reactive oxygen species(ROS)were determined.The protein levels of nuclear factor erythroid 2-related factor 2(Nrf2),solute carrier family 7 member 11(SLC7A11),glutathione peroxidase 4(GPX4),and acyl-coenzyme A synthase long chain family member 4(ACSL4)in the myocardial tissue were determined.Compared with sham group,the model group showed decreased left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS),increased left ventricular end internal dimension in systole(LVIDs),left ventricular internal diameter in diastole(LVIDd),and myocardial collagen deposition,positive expression of collagensⅠandⅢ,elevated apoptosis rate and malondialdehyde(MDA),Fe^(2+),and ROS levels,lowered superoxide dismutase(SOD)and glutathione peroxidase(GSH)levels,down-regulated protein levels of Nrf2,SLC7A11,and GPX4,and up-regulated protein level of ACSL4.Compared with the model group,the above indicators were restored by FYD.Moreover,ML385 reversed the protective effect of FYD on myocardial fibrosis in HF rats.In conclusion,FYD can inh

关 键 词：心力衰竭 附萸汤 心肌纤维化 铁死亡 Nrf2/GPX4通路 

分 类 号：R285.5[医药卫生—中药学]