Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy

Autor(es)

Campos, Erica C. ^[1] ; O'Connell, Joao L. ^[2] ; Malvestio, Lygia M. ^[1] ; Dias Romano, Minna M. ^[2] ; Ramos, Simone G. ^[1] ; Celes, Mara Rubia N. ^[1] ; Prado, Cibele M. ^[1] ; Simoes, Marcus V. ^[3] ; Rossi, Marcos A. ^{[4, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Cellular & Mol Cardiol, Dept Pathol, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Univ Hosp, Div Cardiol, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Internal Med Cardiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 670, n. 2-3, p. 541-553, NOV 30 2011.
• Citações Web of Science: 20

Resumo

The critical importance of dystrophin to cardiomyocyte contraction and sarcolemmal and myofibers integrity, led us to test the hypothesis that dystrophin reduction/loss could be involved in the pathogenesis of doxorubicin-induced cardiomyopathy, in order to determine a possible specific structural culprit behind heart failure. Rats received total cumulative doses of doxorubicin during 2 weeks: 3.75, 7.5, and 15 mg/kg. Controls rats received saline. Fourteen days after the last injection, hearts were collected for light and electron microscopy, immunofluorescence and western blot. The cardiac function was evaluated 7 and 14 days after drug or saline. Additionally, dantrolene (5 mg/kg), a calcium-blocking agent that binds to cardiac ryanodine receptors, was administered to controls and doxorubicin-treated rats (15 mg/kg). This study offers novel and mechanistic data to clarify molecular events that occur in the myocardium in doxorubicin-induced chronic cardiomyopathy. Doxorubicin led to a marked reduction/loss in dystrophin membrane localization in cardiomyocytes and left ventricular dysfunction, which might constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of doxorubicin-induced cardiac depression. Moreover, increased sarcolemmal permeability suggests functional impairment of the dystrophin-glycoprotein complex in cardiac myofibers and/or oxidative damage. Increased expression of calpain, a calcium-dependent protease, was markedly increased in cardiomyocytes of doxorubicin-treated rats. Dantrolene improved survival rate and preserved myocardial dystrophin, calpain levels and cardiac function, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, mainly regarding specific calpain inhibitors, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy. (C) 2011 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 07/59448-0 - O possivel papel do complexo distrofina-glicoproteinas associadas na cardiomiopatia dilatada experimental induzida pelo antineoplasico doxorrubicina.
• Beneficiário: Erica Carolina Campos Pulici
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/13199-1 - Distrofina e suas proteínas associadas na patogênese da cardiomiopatia induzida por doxorrubicina
• Beneficiário: Marcos Antonio Rossi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/17787-8 - Hipertensão arterial, hipertrofia e falência cardíaca e complexo de glicoproteínas associadas à distrofina.
• Beneficiário: Cibele Maria Prado Zinni
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 10/19216-5 - Hipertensão arterial, hipertrofia e falência cardíaca e complexo de glicoproteínas associadas à distrofina
• Beneficiário: Cibele Maria Prado Zinni
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• Processo FAPESP: 09/54010-1 - EMU: sepsis e choque séptico: alterações funcionais e morfológicas do coração. Estudo experimental em camundongos
• Beneficiário: Helio Cesar Salgado
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 09/53544-2 - Avaliação in vitro da expressão de distrofina em cardiomiócitos submetidos a diferentes estímulos
• Beneficiário: Marcos Antonio Rossi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/02942-8 - Avaliação "in vitro" da expressão de distrofina em cardiomiócitos submetidos a diferentes estímulos.
• Beneficiário: Lygia Maria Mouri Malvestio
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 07/58843-2 - O possivel papel do calcio no mecanismo intrinseco de perda primaria de distrofina na patogenese da disfuncao cardiaca na sepsis experimental.
• Beneficiário: Mara Rúbia Nunes Celes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado