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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
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Animals
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Cardiomyopathies / chemically induced*
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Cardiomyopathies / drug therapy*
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Creatine Kinase / blood
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Creatine Kinase / metabolism
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Doxorubicin / toxicity*
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Gene Expression Regulation / drug effects
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Heart / drug effects
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Hemodynamics / drug effects
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Lactate Dehydrogenases / blood
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Lactate Dehydrogenases / metabolism
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Male
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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bcl-2-Associated X Protein / metabolism
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism*
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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bcl-2-Associated X Protein
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Doxorubicin
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Lactate Dehydrogenases
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rho-Associated Kinases
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Creatine Kinase
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rhoA GTP-Binding Protein
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fasudil