PMID:15182862

Citation	Van Remmen, H, Qi, W, Sabia, M, Freeman, G, Estlack, L, Yang, H, Mao Guo, Z, Huang, TT, Strong, R, Lee, S, Epstein, CJ and Richardson, A (2004) Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radic. Biol. Med. 36:1625-34
Abstract	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.
Links	PubMed Online version:10.1016/j.freeradbiomed.2004.03.016
Keywords	Animals; Antioxidants/metabolism; Antioxidants/pharmacology; Body Weight; Cytosol/metabolism; Fibroblasts/metabolism; Gamma Rays; Genotype; Glutathione Peroxidase/genetics; Glutathione Peroxidase/physiology; Mice; Mice, Knockout; Mice, Transgenic; Mitochondria/metabolism; Myocardial Ischemia; Oxidative Stress; Paraquat/pharmacology; Reperfusion Injury; Skin/cytology; Superoxide Dismutase/genetics; Superoxide Dismutase/physiology; Time Factors
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