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

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.