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 significance of calpain-2, we generated transgenic mice with cardiac-specific calpain-2 over-expression. Cardiotoxicity was induced in calpain-2 transgenic mice and their wild-type littermates. Five days and 2 months after doxorubicin injection, myocardial function was assessed by echocardiography. Transgenic over-expression of calpain-2 inhibited apoptosis, increased AKT expression and phosphorylation, and reduced myocardial dysfunction in mice.
Conclusions: Over-expression of calpain-2 reduces doxorubicin-induced cardiotoxicity. The role of calpain-2 may be associated with up-regulation of AKT signaling. Thus, this study suggests a new role of calpain-2 in protecting heart against doxorubicin-induced toxicity.
- © 2013 by American Heart Association, Inc.