title: Preventive effects of fasudil on adriamycin-induced cardiomyopathy: possible involvement of inhibition of RhoA/ROCK pathway.
abstract: The aim of this study was to investigate the involvement of the RhoA/Rho kinase (ROCK) signaling pathway in the progression of ADR-induced heart failure. Rats were administered captopril or fasudil over a period of 6 days, and the ADR was injected intraperitoneally on day 4. Similar to the effect of captopril, fasudil treatment significantly protected against ADR-induced hemodynamic, histopathologic and ultra-structural changes and decreased plasma lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) in a dose-dependent manner in the left ventricle of the heart. While ADR treatment induced ROCKI mRNA expression, fasudil significantly and dose-dependently reduced the incidence of apoptosis and the ratio of bax/bcl-2 protein expression. Moreover, a dose-related decrease in c-jun mRNA expression and an increase in c-FLIP (L) expression were observed in the fasudil groups. Fasudil also downregulated NF-κB activity in a dose-dependent manner. These data indicated that the RhoA/ROCK signaling pathway plays an important role in the progression of heart failure induced by ADR, while fasudil increased resistance to cardiac cell injury. The mechanisms of fasudil-mediated protection against ADR-induced apoptosis may be related to higher c-FLIP (L) and bcl-2 expression, lower c-jun expression and inhibition of NF-κB activation in the heart.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Hebei Medical University, Shijiazhuang 050091, Hebei, China. wangna9@tom.com
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Guan
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhang
authors.forename: Yan-Zhong
authors.initials: YZ
authors.lastname: Chang
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Gu
authors.forename: Fei-Ke
authors.initials: FK
authors.lastname: Hao
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Shi
authors.forename: Feng-Yun
authors.initials: FY
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Chu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000188:drug therapy*; D003402:Creatine Kinase / Q000097:blood / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D045022:Lactate Dehydrogenases / Q000097:blood / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D045022:Lactate Dehydrogenases; D054460:rho-Associated Kinases; D003402:Creatine Kinase; D020742:rhoA GTP-Binding Protein; C049347:fasudil