RESUMEN

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.

Asunto(s)

1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Cardiomiopatías/inducido químicamente , Cardiomiopatías/tratamiento farmacológico , Doxorrubicina/toxicidad , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Creatina Quinasa/sangre , Creatina Quinasa/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Lactato Deshidrogenasas/sangre , Lactato Deshidrogenasas/metabolismo , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/metabolismo , Quinasas Asociadas a rho/genética , Proteína de Unión al GTP rhoA/genética