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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Free Radical Biology and Medicine|
|State||Published - Jun 15 2004|
ASJC Scopus subject areas
- Physiology (medical)