CALPAIN-MEDIATED DYSTROPHIN DISRUPTION MAY BE A POTENTIAL STRUCTURAL CULPRIT BEHIND CHRONIC DOXORUBICIN-INDUCED CARDIOMYOPATHY
Marcos A. Rossi, M.D., Ph.D., University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
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 (5mg/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 dose-dependent marked reduction/loss in dystrophin membrane localization in cardiomyocytes correlated with dose-dependent left ventricular dysfunction, which may constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of a dose-dependent 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 strikingly improved survival rate and preserved myocardial dystrophin and calpain levels, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy.