Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress

• Published in: Free radical biology & medicine 2004-06, Vol.36 (12), p.1625-1634
• Main Authors: Van Remmen, Holly, Qi, Wenbo, Sabia, Marian, Freeman, Gregory, Estlack, Larry, Yang, Hong, Mao Guo, Zhong, Huang, Ting-Ting, Strong, Randy, Lee, Shuko, Epstein, Charles J., Richardson, Arlan
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2004.03.016

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 γ 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 γ 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.