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

• Published in: European journal of pharmacology 2011-11, Vol.670 (2-3), p.541-553
• Main Authors: Campos, Erica C., O'Connell, João L., Malvestio, Lygia M., Romano, Minna M. Dias, Ramos, Simone G., Celes, Mara Rúbia N., Prado, Cibele M., Simões, Marcus V., Rossi, Marcos A.
• Format: Article
• Language: English
• Subjects: actin; Actins - metabolism; Animals; Anthracyclines; Biological and medical sciences; Body Weight - drug effects; calpain; Calpain - metabolism; Cancer; cardiac output; Cardiology. Vascular system; cardiomyocytes; Cardiomyopathies - chemically induced; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Cardiomyopathy; Cell Membrane Permeability - drug effects; Dantrolene - pharmacology; Doxorubicin; Doxorubicin - adverse effects; Dystrophin; Dystrophin - metabolism; Electrocardiography; electron microscopy; fluorescent antibody technique; Heart; Heart - drug effects; Heart - physiopathology; Heart failure; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Lung - drug effects; Lung - pathology; Male; Medical sciences; Myocarditis. Cardiomyopathies; myocardium; Myocardium - metabolism; Myocardium - pathology; Myocardium - ultrastructure; myofibrils; myosin; Myosins - metabolism; Organ Size - drug effects; pathogenesis; permeability; Pharmacology. Drug treatments; Rats; Rats, Wistar; ryanodine receptors; Sarcolemma - drug effects; Sarcolemma - metabolism; Survival Analysis; survival rate; Time Factors; Western blotting
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.09.021

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 2weeks: 3.75, 7.5, and 15mg/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 14days 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 (15mg/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.