| 15182862 |
Van Remmen H, Qi W, Sabia M, Freeman G, Estlack L, Yang H, Mao Guo Z, Huang TT, Strong R, Lee S, Epstein CJ, Richardson A: Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radic Biol Med. 2004 Jun 15;36(12):1625-34.
To examine the effect of compound deficiencies in antioxidant defense, we have generated mice (Sod2 (+/-)/Gpx1 (-/-)) that are deficient in Mn superoxide dismutase (MnSOD) and glutathione peroxidase 1 (Gpx1) by breeding Sod2 (+/-) and Gpx1 (-/-) mice together. Although Sod2 (+/-)/Gpx1 (-/-) mice showed a 50% reduction in MnSOD and no detectable Gpx1 activity in either mitochondria or cytosol in all tissues, they were viable and appeared normal. Fibroblasts isolated from Sod2 (+/-)/Gpx1 (-/-) mice were more sensitive (4- to 6-fold) to oxidative stress (t-butyl hydroperoxide or gamma irradiation) than fibroblasts from wild-type mice, and were twice as sensitive as cells from Sod2 (+/-) or Gpx1 (-/-) mice. Whole-animal studies demonstrated that survival of the Sod2 (+/-)/Gpx1 (-/-) mice in response to whole body gamma irradiation or paraquat administration was also reduced compared with that of wild-type, Sod2 (+/-), or Gpx1 (-/-) mice. Similarly, endogenous oxidative stress induced by cardiac ischemia/reperfusion injury led to greater apoptosis in heart tissue from the Sod2 (+/-)/Gpx1 (-/-) mice than in that from mice deficient in either MnSOD or Gpx1 alone. These data show that Sod2 (+/-)/Gpx1 (-/-) mice, deficient in two mitochondrial antioxidant enzymes, have significantly enhanced sensitivity to oxidative stress induced by exogenous insults and to endogenous oxidative stress compared with either wild-type mice or mice deficient in either MnSOD or Gpx1 alone. |
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