Abstract 17857: Calpain-2 Protects Against Doxorubicin-Induced Cardiac Toxicity

Background: Doxorubicin, a highly effective chemotherapeutic agent, can cause cumulative dose-dependent cardiotoxicity, which may present as cardiomyopathy. We have recently demonstrated that inhibition of calpain increases apoptosis in cardiomyocytes and aggravates myocardial dysfunction and mortality in mice with calpastatin over-expression. This study suggests that endogenous calpain may provide cardioprotection in doxorubicin-induced toxicity. Objective: The present study was to investigate which isoforms of calpain would protect against doxorubicin-induced cardiotoxicity. Methods and Results: In cultured neonatal cardiomyocytes, over-expression of calpain-2 attenuated apoptosis induced by doxorubicin whereas calpain-1 slightly enhanced apoptosis. The inhibitory effect of calpain-2 on apoptosis correlated with up-regulation of AKT signaling and a reduction in histone H2AX phosphorylation. These results indicate a protective role of calpain-2 in doxorubicin-induced cardiotoxicity. To study the in vivo ...