The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice.

Abstract

Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and glutathione peroxidase did not change in the transgenic mice. Electron microscopy revealed dose-dependent ultrastructural alterations with marked mitochondrial damage in nontransgenic mice treated with ADR, but not in the transgenic littermates. Biochemical analysis indicated that the levels of serum creatine kinase and lactate dehydrogenase in ADR-treated mice were significantly greater in nontransgenic than their transgenic littermates expressing a high level of human MnSOD after ADR treatment. These results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury. ( J. Clin. Invest. 1996. 98:1253-1260.) Key words: free radicals • mitochondria • antioxidants • heart • antineoplastic agents

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…Ultrastructural injury in cardiac tissues was evaluated by electron microscopic analysis on four mice from each treatment groups, using methods described by Yen et al [33] with minor modifications. Heart tissue was cut into 1 mm 3 pieces and fixed in fullstrength Karnovsky′s fixative [4% paraformaldehyde and 5% glutaraldehyde in 0.1 mol/L sodium phosphate buffer (pH 7.4)] for 4 to 5 hours, and then postfixed in Caulfield′s osmium tetroxide with sucrose for 30 to 60 minutes at 4°C.…”

The protective effect of cardiac gene transfer of CuZn–sod in comparison with the cardioprotector monohydroxyethylrutoside against doxorubicin-induced cardiotoxicity in cultured cells

“…Previous experiments, showed that only high level of Mn-sod protected against LDH and CK increase in the serum of transgenic mice. 16 Also complete protection was only obtained with a 10-fold increase in CuZn-sod in transgenic mice 32 while less than five-fold increase in sod activity did not fully protect against free radicals produced by doxorubicin 17 or hypoxia/reoxygenation. 14 MonoHER is a semisynthetic flavonoid.…”

“…30,31 Indeed, when Mn-sod was endogenously expressed in high levels in transgenic mice a partial protection against doxorubicin-induced cardiotoxicity could be achieved. 16,17 This incomplete protection might be the result of the confinement of Mn-sod to the mitochondria or of the possibility that the levels of Mnsod are still insufficient to show the desired cardioprotection.…”

“…15 Others have also shown that the overexpression of high levels of Mn-sod protected transgenic mice against doxorubicin cardiotoxicity while lower levels did not. 16 The overexpression of Mn-sod has also been shown to partially protect against doxorubicin inhibition of the activity of the respiratory complex in transgenic mice. 17 Yet, no data have shown the protective effect of the overexpression of CuZn-sod against doxorubicin-induced cardiotoxicity.…”

A toxicoproteomic study on cardioprotective effects of pre-administration of docetaxel in a mouse model of adriamycin-induced cardiotoxicity

“…However, it was not yet clear exactly what mechanism was responsible for either the cardioprotective effects or the over-expression of GAPDH observed 18 in the DOC -ADR group. Previous r esearch ha s s hown t hat the over-expression of antioxidant e nzymes (i.e., superoxide d ismutase and c atalase) in TG mice protected heart from A DR-induced cardiotoxicity [ 58,59]. Therefore, the s ame transgenic approach or another approach with the addition of N 6 -naphthalenemethyl-2'-methoxybenzamido-β-NAD + for GAPDH inhibition [60] may be useful in validating and elucidating any cardioprotective effects associated with GAPDH.…”