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

Holly Van Remmen, Wenbo Qi, Marian Sabia, Gregory Freeman, Larry Estlack, Hong Yang, Zhong Mao Guo, Ting Ting Huang, Randy Strong, Shuko Lee, Charles J. Epstein, Arlan Richardson

Research output: Contribution to journalArticle

106 Scopus citations

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 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 languageEnglish (US)
Pages (from-to)1625-1634
Number of pages10
JournalFree Radical Biology and Medicine
Volume36
Issue number12
DOIs
StatePublished - Jun 15 2004

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Van Remmen, H., Qi, W., Sabia, M., Freeman, G., Estlack, L., Yang, H., Guo, Z. M., Huang, T. T., Strong, R., Lee, S., Epstein, C. J., & Richardson, A. (2004). Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radical Biology and Medicine, 36(12), 1625-1634. https://doi.org/10.1016/j.freeradbiomed.2004.03.016