| Adriamycin (ADR) is one of the most effective anticancer drugs used for clinical chemotherapy. Beside its potent antineoplastic activity, ADR-associated cardiac injury is also well documented. The prevailing hypothesis implicates the involvement of reactive oxygen species (ROS) in cardiac injury caused by ADR. In the present study, we investigated the roles of the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD) and tumor necrosis factor (TNF), a well-known MnSOD inducing factor, in ADR cardiotoxicity. MnSOD overexpressing (TgM) mice and TNF receptors knockout (DKO) mice were used as experimental models for both in vivo and in vitro studies. Treatment with ADR caused remarkable ultrastructural injury in the heart of the normal mice. The cardiac injury was greater in DKO mice bur less severe in TgM mice compared with wild type (NTg) mice. ADR also increased DNA fragmentation and the activation of caspase 3. Exacerbation of the injury in DKO mice was associated with altered responses of NFκB and AP-1 activation, but was not associated with the alteration of intracellular redox status or the levels of BCL-2 proteins. Myocardium damage caused by ADR might be attributed to its direct toxic effect on cardiomyocytes. Primary cardiomyocytes isolated from adult mice showed ultrastructural injury, decrease of mitochondrial membrane potential, and apoptotic cell death after treated with ADR. Consistent with the results of the in vivo study, the cardiomyocytes isolated from DKO mice exhibited more apoptosis, while cardiomyocytes isolated from TgM mice showed a reduced frequency of apoptosis compared with cells from wild type mice. The progeny from the crossing of TgM mice with DKO mice exhibited less severe cardiac injury compared with DKO mice, indicating that overexpression of MnSOD reduced the exacerbation of cardiac injury. In conclusion, the results from the present study suggest that (1) both MnSOD and TNF exert a protective role in ADR-induced cardiotoxicity, (2) ADR associated myocardium dysfunction may result from direct toxic effects of ADR on cardiomyocytes, (3) overexpression of MnSOD confers a compensatory effect for the deficiency of TNF receptors, implying the mitochondria as common targets for MnSOD and endogenous TNF-mediated cardioprotection against ADR toxicity. |
