基于成纤维生长因子21抑制线粒体损伤途径探讨强心汤对慢性心力衰竭的治疗作用  

Study on the therapeutic effect of Qiangxin Decoction on chronic heart failure based on the inhibition of mitochondrial damage pathway by fibroblast growth factor 21

作　　者：毛美玲 卢健棋[2] 韩景波[3] 卢洁 卢俊燊 谢丽钰 陈佳永 肖湘 石炜琦 杨尚冰 董礼 MAO Meiling;LU Jianqi;HAN Jingbo;LU Jie;LU Junshen;XIE Liyu;CHEN Jiayong;XIAO Xiang;SHI Weiqi;YANG Shangbing;DONG Li(Graduate School of Guangxi University of Traditional Chinese Medicine,Nanning 530299,China)

机构地区：[1]广西中医药大学研究生院,南宁530299 [2]广西中医药大学第一附属医院心内科 [3]广西中医药大学第一附属医院经典科 [4]广西中医药大学附设中医学校

出　　处：《环球中医药》2025年第2期224-233,共10页Global Traditional Chinese Medicine

基　　金：国家自然科学基金(82160887);广西自然科学基金(2021GXNSFAA220111);广西岐黄学者培养项目(2022015-003-02);国家中医药传承创新中心项目(2023019-10);广西中医药大学研究生教育创新计划(YCBXJ2023024);广西高水平中医药重点学科—中医心病学(2024016-02-02)。

摘　　要：目的 探讨强心汤基于成纤维生长因子21(fibroblast growth factor 21,FGF21)抑制线粒体损伤、氧化应激和心肌纤维化治疗慢性心力衰竭(chronic heart failure, CHF)的作用机制。方法 将35只C57BL/J小鼠随机分为对照组、模型组、强心汤低、高剂量组、西药组,每组7只。采用结扎冠状动脉左前降支方法建立慢性心力衰竭小鼠模型,强心汤低、高剂量组每天分别给予强心汤21.69 g/kg、43.38 g/kg、西药组每天给予沙库巴曲缬沙坦15.17 mg/kg灌胃,对照组、模型组每次给予等体积纯净水,每日1次。连续干预4周后采用酶联免疫吸附试验(enzyme linked immunosorbent assay, ELISA)法检测血清中N末端脑钠肽前体(N-terminal pro-brain natriuretic peptide, NT-proBNP)的水平;马松染色观察各组小鼠心肌组织纤维化情况;荧光终端DUTP缺口端标签(terminal dUTP nick end labeling, TUNEL)观察小鼠心肌细胞凋亡情况;透射电镜观察心肌组织线粒体损伤情况;免疫组化法和蛋白印迹(western blot, WB)法检测心肌组织中FGF21、血红素加氧酶1(heme oxygenase-1,Hmox 1)、硫氧还蛋白还原酶(thioredoxin reductase, Txnrd)蛋白的表达情况。结果 与对照组比较,模型组小鼠NT-proBNP水平明显升高(P<0.01);心肌组织纤维化、心肌细胞凋亡严重;线粒体碎裂、嵴消失、数量减少、体积大小不一、肌丝排列不齐;FGF21水平明显升高(P<0.01),Hmox1、Txnrd1表达水平明显降低(P<0.01)。与模型组比较,药物干预各组血清中NT-proBNP水平降低(P<0.01)、心肌组织纤维化和心肌细胞凋亡情况明显减轻;线粒体数量增加、体积大小较一致、肌丝排列较为致密,整体形态接近对照组;FGF21水平明显降低(P<0.01),Hmox1、Txnrd1表达水平明显升高(P<0.01)。结论 强心汤可改善CHF小鼠心肌细胞凋亡和纤维化,其机制可能与调节FGF21的表达进而抑制线粒体损伤和氧化应激情况有关。Objective Explore the mechanism of Qiangxin Decoction in treating chronic heart failure(CHF)by inhibiting mitochondrial damage,oxidative stress,and myocardial fibrosis based on fibroblast growth factor 21(FGF21).Methods Thirty five C57BL/J mice were randomly divided into the control group,the model group,the low-dose and high-dose Qiangxin Decoction groups,and the Western medicine group,with seven mice in each group.The mice model of chronic heart failure was established by ligating the left anterior descending coronary artery.The low-dose and high-dose Qiangxin Decoction groups and the Western medicine group received daily gavage administrations of Qiangxin Decoction at 21.69 g/kg and 43.38 g/kg,respectively,along with sacubitril valsartan at 15.17 mg/kg.Mice in the control group and the model group were given equal volumes of purified water once a day.After four weeks of continuous intervention,the level of NT-proBNP in serum was measured using ELISA;Masson staining was employed to observe myocardial fibrosis in mice across all groups;Fluorescent TUNEL was used to observe cardiomyocyte apoptosis;Transmission electron microscopy was used to observe mitochondrial damage in myocardial tissue;Immunohistochemistry and Western Blot methods were used to detect the expression of fibroblast growth factor 21(FGF21),heme oxygenase 1(Hmox1),and thioredoxin reductase 1(Txnrd1)proteins in myocardial tissue.Results Compared with the control group,the NT-proBNP levels in the model group were increased significantly(P<0.01);Myocardial fibrosis and cardiomyocyte apoptosis were severe;Mitochondria were fragmented,with cristae absent,fewer in number,variable in size,and myofilaments irregularly aligned;FGF21 levels were increased significantly(P<0.01),while the expression levels of Hmox1 and Txnrd1 were significantly decreased(P<0.01).Compared with the model group,the levels of NT proBNP in the serum of each drug intervention group were decreased(P<0.01),myocardial fibrosis,and cardiomyocyte apoptosis were significantly alleviated

关 键 词：强心汤 慢性心力衰竭 成纤维细胞生长因子21 血红素加氧酶1 硫氧还蛋白还原酶1 线粒体 中药复方 

分 类 号：R285.5[医药卫生—中药学]