Manganese Superoxide Dismutase Protects Mitochondrial Complex I against Adriamycin-Induced Cardiomyopathy in Transgenic Mice

Yen, Hsiu Chuan; Oberley, Terry D.; Gairola, C. Gary; Szweda, Luke I.; Clair, Daret K. St.

doi:10.1006/abbi.1998.1011

Cited by 135 publications

(96 citation statements)

References 35 publications

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“…It has been reported that mitochondrial defects leads to cardiomyopathy and heart failure [37], suggesting mitochondrial damages may play a pivotal role in ADRinduced cardiomyopathy and heart failure. We have previously demonstrated that modulation of MnSOD, the primary antioxidant enzyme that resides only in mitochondria, protects against ADR cardiotoxicity [17,33,36]. Consistent with the previous results, our current result demonstrated that PBA increased MnSOD at both protein and activity levels (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…Our previous study has shown that induction of MnSOD, the primary antioxidant enzyme residing in mitochondrion, mediates the cardioprotective mechanism of Tamoxifen, an anticancer drug used in breast cancer treatment [17]. Using heterozygous MnSOD knockout (MnSOD +/-) and human MnSOD transgenic mice, we have also demonstrated that increase of MnSOD activity alone leads to protection against ADR cardiotoxicity [17,33,36]. To explore whether MnSOD played a role in the observed cardioprotective effects of PBA, we examined MnSOD levels in the heart samples after mice were treated with ADR or/and PBA.…”

Section: Mnsodmentioning

confidence: 99%

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

Daosukho

Chen

Noel

et al. 2007

Free Radical Biology and Medicine

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Cardiac injury is a major complication for oxidative stress-generating anticancer agents exemplified by Adriamycin (ADR). Recently, several histone deacetylase inhibitors (HDACIs) including phenylbutyrate (PBA) have shown promise in the treatment of cancer with little known toxicity to normal tissues. PBA has been shown to protect against oxidative stress in normal tissues. Here, we examined whether PBA might protect heart against ADR toxicity in a mouse model. The mice were i.p. injected with ADR (20 mg/kg). PBA (400 mg/kg/day) was i.p. injected one day before and daily after the ADR injection for two days. We found that PBA significantly decreased the ADR-associated elevation of serum lactase dehydrogenase (LDH) and creatine kinase (CK) activities, and diminished ADR-induced ultrastructual damages of cardiac tissue by more than 70%. Importantly, PBA completely rescued ADR-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening, and increased cardiac MnSOD protein and activity. Our results reveal a previously unrecognized role of HDACIs in protecting against ADR-induced cardiac injury, and suggest that PBA may exert its cardioprotective effect, in part, by the increase of MnSOD. Thus, combining HDACIs with ADR could add a new mechanism to fight cancer while simultaneously decrease ADR-induced cardiotoxicity.

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Section: Discussionsupporting

confidence: 92%

Section: Mnsodmentioning

confidence: 99%

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

Daosukho

Chen

Noel

et al. 2007

Free Radical Biology and Medicine

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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Doxorubicin-induced cardiotoxicity is related to its production of free radicals that specifically affect heart tissue because of its low antioxidant status. Monohydroxyethylrutoside (monoHER), a potent antioxidant flavonoid, is under development as a protector against doxorubicin-induced cardiotoxicity. The overexpression of high levels of superoxide dismutase (sod) protects against free radical damage in transgenic mice. Seeking alternatives besides the few cardioprotectors that are presently under investigation, the aim of the present study was to investigate the protective effect of cardiac gene transfer of CuZn-sod compared with that of the presently most promising cardioprotector monoHER against doxorubicin-induced cardiotoxic effects on neonatal rat cardiac myocytes (NeRCaMs) in vitro. NeRCaMs were infected with different multiplicity of infections (MOIs) of adenovirus encoding CuZn-sod (AdCuZn-sod). A control infection with an adenovirus vector encoding a nonrelated protein was included. The overexpression of CuZn-sod was characterized within 3 days postinfection.For doxorubicin treatment, NeRCaMs were divided into three groups. The first group was infected with AdCuZn-sod before treatment with doxorubicin (0-50 mM). The second and third groups were treated with doxorubicin (0-50 mM) alone and with 1 mM monoHER, respectively. The LDH release and survival of treated cells were measured 24 and 48 hours after doxorubicin treatment. The beating rate was followed during the 3 days after doxorubicin (0-100 mM) treatment.At the third day after infection with an MOI of 25 plaque-forming unit (PFU) of AdCuZn-sod/cell, the activity of CuZn-sod significantly increased (five-fold, P ¼ .029). Higher MOI produced cytopathic effects (CPEs).Doxorubicin alone produced significant concentration-and time-dependent reduction in NeRCaMs beating rate and survival (Po.0005). Doxorubicin (X50 mM)-treated cells ceased to beat after 24 hours. This cytotoxicity was associated with an increase in the LDH release from the treated cells (Po.0005).The five-fold increase in the activity of CuZn-sod did not protect against any of the cytotoxic effects of doxorubicin on NeRCaMs. In contrast, monoHER (1 mM) protected against the lethal effects of doxorubicin on the survival, LDH release and the beating rate of NeRCaMs (Po.004) during 48 hours after doxorubicin treatment. Doxorubicin-treated (r100 mM) cells continued beating for 472 hours in the presence of monoHER.The present study showed the lack of adenoviral CuZn-sod gene-transfer to protect myocardiocytes against doxorubicin-induced toxicity and confirms the efficacy of monoHER cardioprotection. Thus, a gene-therapy strategy involving overexpression of CuZnsod to protect against doxorubicin-induced cardiotoxicity is not feasible with the currently available adenovirus vectors.

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Association of Manganese Superoxide Dismutase Expression With Progression of Carcinogenesis in Barrett Esophagus

Hermann

Ray

et al. 2005

Arch Surg

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Manganese Superoxide Dismutase Protects Mitochondrial Complex I against Adriamycin-Induced Cardiomyopathy in Transgenic Mice

Cited by 135 publications

References 35 publications

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

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

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

Association of Manganese Superoxide Dismutase Expression With Progression of Carcinogenesis in Barrett Esophagus

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