title: Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Pathology (Laboratory of Cellular and Molecular Cardiology), Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Erica C
authors.initials: EC
authors.lastname: Campos
authors.forename: João L
authors.initials: JL
authors.lastname: O'Connell
authors.forename: Lygia M
authors.initials: LM
authors.lastname: Malvestio
authors.forename: Minna M Dias
authors.initials: MM
authors.lastname: Romano
authors.forename: Simone G
authors.initials: SG
authors.lastname: Ramos
authors.forename: Mara Rúbia N
authors.initials: MR
authors.lastname: Celes
authors.forename: Cibele M
authors.initials: CM
authors.lastname: Prado
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Simões
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Rossi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002154:Calpain / Q000378:metabolism*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects*; D016189:Dystrophin / Q000378:metabolism*; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009218:Myosins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000199:Actins; D016189:Dystrophin; D004317:Doxorubicin; D002154:Calpain; D009218:Myosins; D003620:Dantrolene