抗纤益心方通过调控xCT/GPX4通路介导的铁死亡改善扩张型心肌病小鼠心功能的作用机制  

Kangxian Yixin(抗纤益心)Decoction Improves Cardiac Function in the Mouse Model of Dilated Cardiomyopathy by Regulating xCT/GPX4-Mediated Ferroptosis

作　　者：常红波[1] 王振涛[2] 吴鸿[1] 曾垂义[2] 施伟丽 高海霞 CHANG Hongbo;WANG Zhentao;WU Hong;ZENG Chuiyi;SHI Weili;GAO Haixia(Henan University of Chinese Medicine,Zhengzhou 450046;Henan Province Hospital of Traditional Chinese Medicine,Zhengzhou 450002)

机构地区：[1]河南中医药大学,郑州450046 [2]河南省中医院,郑州450002

出　　处：《中药药理与临床》2024年第12期21-26,共6页Pharmacology and Clinics of Chinese Materia Medica

基　　金：国家自然科学基金(编号:82205082);河南省科技研发计划(优势学科培育类)项目(编号:232301420066);河南省高等学校重点科研项目(编号:24A360001)。

摘　　要：目的:从调控铁死亡角度探讨抗纤益心方对扩张型心肌病(Dilated cardiomyopathy,DCM)小鼠心功能的影响及作用机制。方法:将48只cTnTR141W转基因DCM小鼠按照随机数字表法分为模型对照组、抗纤益心方2.7、5.4 g/kg组、卡托普利0.01 g/kg组,每组12只,另设12只C57BL/6J小鼠为正常对照组,各组小鼠灌胃8 w后,小动物超声仪检测左室收缩末期内径(LVESD)、左室舒张末期内径(LVEDD)、射血分数(EF)、缩短率(FS);HE染色观察心肌病理形态;普鲁士蓝染色检测心肌铁沉积;透射电镜观察线粒体超微结构;酶联免疫吸附测定法(ELISA)检测小鼠血清脑钠肽(BNP)、丙二醛(MDA)和还原型谷胱甘肽(GSH)含量;荧光探针检测活性氧(ROS)水平;Western blot法检测心肌组织胱氨酸谷氨酸反向转运蛋白(xCT)、谷胱甘肽过氧化物酶4(GPX4)、铁蛋白重链1(FTH1)蛋白表达。结果:与正常对照组比较,模型对照组LVESD和LVEDD升高、FS和EF降低,心肌病理损伤明显,铁沉积增多,血清BNP、MDA含量、心肌ROS水平显著升高、血清GSH含量明显降低(P<0.05或P<0.01),心肌线粒体破裂皱缩、排列紊乱,心肌xCT、GPX4、FTH1蛋白表达显著下调(P<0.01);与模型对照组比较,抗纤益心方各组LVESD和LVEDD降低、FS和EF增加(P<0.05或P<0.01),心肌损伤减轻,铁沉积减少,血清BNP、MDA含量降低,心肌ROS水平降低,血清GSH含量升高(P<0.05或P<0.01),心肌线粒体破裂皱缩及排列紊乱减轻,心肌xCT、GPX4、FTH1蛋白表达上调(P<0.05或P<0.01)。结论:抗纤益心方能够改善DCM小鼠心脏功能,其作用机制可能与激活xCT/GPX4信号通路抑制铁死亡有关。Objective:To reveal the effect of Kangxian Yixin(抗纤益心)Decoction(KYD)on the cardiac function of the mouse model of dilated cardiomyopathy(DCM)and decipher the mechanism from ferroptosis.Methods:Forty-eight cTnT^(R141W)transgenic DCM mice were randomized into model,KYD(2.7 and 5.4 g/kg),and captopril(10.1 g/kg)groups,with 12 mice in each group.Another 12 C57BL/6J mice were selected as the normal control group.Mice in each group were administrated with corresponding drugs by gavage for 8 weeks.The left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter(LVESD),ejection fraction(EF),and fractional shortening(FS)were measured by ultrasound for small animals.Hematoxylin-eosin staining was conducted to reveal the pathological changes in the myocardial tissue.The iron deposition was detected by Prussian blue staining,and the mitochondrial morphological structure was observed by electron microscopy.The serum levels of brain-derived natriuretic peptide(BNP),malondialdehyde(MDA),and reduced glutathione(GSH)were measured by ELISA.The level of reactive oxygen species(ROS)was measured by a fluorescent probe.The protein levels of cystine/glutamate antiporter(xCT),glutathione peroxidase 4(GPX4),and ferritin heavy chain 1(FTH1)were determined by Western blotting.Result:Compared with the normal control group,the model group showcased increased LVESD and LVEDD,decreased FS and EF(P<0.05),obvious myocardial injury,enhanced iron deposition,risen levels of BNP,MDA,and ROS,declined level of GSH(P<0.01),disrupted,shrinking,and disarranged mitochondria,and down-regulated protein levels of xCT,GPX4,and FTH1(P<0.01).Compared with the model group,KYD reduced LVESD and LVEDD,increased FS and EF(P<0.05),alleviated myocardial injury,decreased iron deposition,lowered the levels of BNP,MDA,and ROS,elevated the level of GSH(P<0.05 or P<0.01),alleviated the damage,shrinking,and disarrangement of mitochondria,and up-regulated the protein levels of xCT,GPX4,and FTH1(P<0.05 or P<0.01).Conclusion:KYD can improve th

关 键 词：抗纤益心方 扩张型心肌病 心脏功能 铁死亡 xCT/GPX4信号通路 

分 类 号：R285.5[医药卫生—中药学]