盐酸阿霉素通过DRP1/FUNDC1信号通路调节线粒体动力学诱导大鼠慢性心力衰竭  

Doxorubicin induces chronic heart failure in rats by regulating mitochondrial dynamics via DRP1/FUNDC1 pathway

作　　者：夏冉 朱国旗[1] 高兵 汪恒 朱梦 李凌基 王祝 王茎[3] 戴小华[4] XIA Ran;ZHU Guo-qi;GAO Bing;WANG Heng;ZHU Meng;LI Ling-ji;WANG Zhu;WANG Jing;DAI Xiao-hua(Clinical College of Chinese Medicine,Hefei 230038,China;College of Acupuncture and Massage,Hefei 230038,China;Xin’an Medical Education Laboratory of Anhui University of Chinese Medicine,Hefei 230038,China;The First Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230031,China)

机构地区：[1]安徽中医药大学中医学院,安徽合肥230038 [2]安徽中医药大学针炙推拿学院,安徽合肥230038 [3]安徽中医药大学新安医学教育部实验室,安徽合肥230038 [4]安徽中医药大学第一附属医院,安徽合肥230031

出　　处：《中国药理学通报》2022年第11期1661-1666,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金面上项目(No.81574084);安徽省自然科学基金面上项目(No.1608085 MH 230);安徽省重点研究与开发计划项目(No.202004j07020045);安徽中医药大学校级探索性科研项目(No.2021zxts27)。

摘　　要：目的探讨盐酸阿霉素(doxorubicin hydrochloride,DOX)对大鼠心功能的损害程度,并初步探讨其可能机制。方法实验一:SD大鼠(n=48)随机分为Control组(生理盐水)、DOX 1组(DOX腹腔注射累积剂量12 mg·kg^(-1))、DOX 2组(15 mg·kg^(-1))、DOX 3组(18 mg·kg^(-1))。采用超声心动图检测各组大鼠心脏结构和心功能;ELISA法检测B型脑钠肽(B-type natriuretic peptide,BNP);HE染色观察心肌组织形态学变化。综合选出最优剂量组(DOX 2组)。实验二:SD大鼠(n=36)随机分为Control组(生理盐水)、DOX 2组(15 mg·kg^(-1))、DOX 2+Mdivi-1组(15 mg·kg^(-1)+每日腹注Mdivi-1(1 mg·kg^(-1))。Western blot法检测心肌线粒体动力学相关蛋白表达。结果与Control组相比,DOX各组心脏扩大,心功能下降;DOX组镜下见心肌细胞肥大、心肌纤维排列松散,且大鼠DOX体内累积剂量越高,大鼠心衰程度越重,死亡率越高。与Control组相比,DOX 2组线粒体分裂蛋白1(dynamin-related protein 1,DRP1)及相关信号通路蛋白(FUN14 domain containing 1,FUNDC1)表达增强,视神经萎缩1(optic atrophy 1,OPA1)表达降低,使用了线粒体动力学抑制剂(Mdivi-1)后,FUNDC1、DRP1蛋白表达量降低,OPA1蛋白表达增强。结论DOX可以导致慢性心衰,其机制可能与DRP1/FUNDC1介导的线粒体分裂、融合相关。Aim To investigate the damage degree of doxorubicin hydrochloride(DOX)on cardiac function in rats,and to explore its possible mechanism.Methods Experiment 1:SD rats(n=48)were randomly divided into control group(normal saline),DOX 1 group(DOX cumulative dose 12 mg·kg^(-1) intraperitoneal injection),DOX 2 group(15 mg·kg^(-1))and DOX 3 group(18 mg·kg^(-1)).Cardiac structure and cardiac function were detected by echocardiography.B-type natriuretic peptide(BNP)was detected by ELISA.The morphological changes of myocardium were observed by Hematoxylin-eosin(HE)staining.The optimal dose group(DOX 2 group)was selected comprehensively.Experiment 2:SD rats(n=36)were randomly divided into control group(normal saline),DOX 2 group(15 mg·kg^(-1))and DOX 2+Mdivi-1 group(15 mg·kg^(-1)+daily abdominal injection of Mdivi-1(1 mg·kg^(-1))).Western blot was used to detect the protein expression of myocardial mitochondrial dynamics.Results Compared with the control group,hearts in DOX groups were enlarged and the heart function was reduced.Under the microscope,hypertrophy of cardiac cells and loose arrangement of cardiac fibers were observed in DOX group,and the higher the cumulative dose of DOX in rats,the more severe the degree of heart failure and the higher the mortality rate of rats.Compared with control group,the expression of mitochondrial dynamin-related protein 1(DRP1)and related signaling pathway protein FUN14 domain containing 1(FUNDC1)in DOX 2 group increased.The expression of optic atrophy 1(OPA1)decreased,the expression of FUNDC1 and DRP1 protein decreased,and the expression of OPA1 protein was enhanced after the use of mitochondrial dynamics inhibitor(Mdivi-1).Conclusions DOX can cause chronic heart failure,and the mechanism may be related to DRP1/FUNDC1 mediated mitochondrial fission and fusion.

关 键 词：盐酸阿霉素 慢性心衰 心功能 线粒体分裂 线粒体融合 信号通路 

分 类 号：R-332[医药卫生] R322.11R329.24R541.61R979.14