doxorubicin induces chronic heart failure in rats by regulating mitochondrial dynamics via drp1/fundc1 pathway / 中国药理学通报

ABSTRACT

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.