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Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice.

ABSTRACT: Caspase-2 has been implicated in apoptosis and in non-apoptotic processes such as cell cycle regulation, tumor suppression and ageing. Using caspase-2 knockout (casp2(-/-)) mice, we show here that the putative anti-ageing role of this caspase is due in part to its involvement in the stress response pathway. The old casp2(-/-) mice show increased cellular levels of oxidized proteins, lipid peroxides and DNA damage, suggesting enhanced oxidative stress. Furthermore, murine embryonic fibroblasts from casp2(-/-) mice showed increased reactive oxygen species generation when challenged with pro-oxidants. Reduced activities of antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were observed in the old casp2(-/-) mice. Interestingly, in the old casp2(-/-) animals expression of FoxO1 and FoxO3a was significantly reduced, whereas p21 levels and the number of senescent hepatocytes were elevated. In contrast to young wild-type mice, the casp2(-/-) animals fed an on ethanol-based diet failed to show enhanced GSH-Px and SOD activities. Thus, caspase-2, most likely via FoxO transcription factors, regulates the oxidative stress response in vivo.

SUBMITTER: Shalini S

PROVIDER: S-EPMC3392626 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice.

Shalini S S Dorstyn L L Wilson C C Puccini J J Ho L L Kumar S S

Cell death and differentiation 20120217 8

Caspase-2 has been implicated in apoptosis and in non-apoptotic processes such as cell cycle regulation, tumor suppression and ageing. Using caspase-2 knockout (casp2(-/-)) mice, we show here that the putative anti-ageing role of this caspase is due in part to its involvement in the stress response pathway. The old casp2(-/-) mice show increased cellular levels of oxidized proteins, lipid peroxides and DNA damage, suggesting enhanced oxidative stress. Furthermore, murine embryonic fibroblasts fr ...[more]

PMID: 22343713

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Project description:Polyhydroxylated derivatives of fullerene C60, named fullerenols (C60[OH]n), have stimulated great interest because of their potent antioxidant properties in various chemical and biological systems, which enable them to be used as a new promising pharmaceutical for the future treatment of oxidative stress-related diseases, but the details remain unknown. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a principal transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element and plays a crucial role in cellular defence against oxidative stress. In this study we investigated whether activation of the Nrf2/antioxidant response element pathway contributes to the cytoprotective effects of C60(OH)24. Our results showed that C60(OH)24 enhanced nuclear translocation of Nrf2 and upregulated expression of phase II antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1, and ?-glutamate cysteine ligase in A549 cells. Treatment with C60(OH)24 resulted in phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK), extracellular signal-regulated kinases, and c-Jun-N-terminal kinases. By using inhibitors of cellular kinases, we showed that pretreatment of A549 cells with SB203580, a specific inhibitor of p38 MAPK, abolished nuclear translocation of Nrf2 and induction of HO-1 protein induced by C60(OH)24, indicating an involvement of p38 MAPK in Nrf2/HO-1 activation by C 60(OH)24. Furthermore, pretreatment with C60(OH)24 attenuated hydrogen peroxide-induced apoptotic cell death in A549 cells, and knockdown of Nrf2 by small interfering ribonucleic acid diminished C60(OH)24-mediated cytoprotection. Taken together, these findings demonstrate that C60(OH)24 may attenuate oxidative stress-induced apoptosis via augmentation of Nrf2-regulated cellular antioxidant capacity, thus providing insights into the mechanisms of the antioxidant properties of C60(OH)24.

Dataset Information

Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice.

Publications

Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice.

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