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, John R Strong, Shuko Lee, Charles J. Epstein, Arlan Richardson

Research output: Contribution to journalArticle

105 Citations (Scopus)

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

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Oxidative stress
Oxidative Stress
Antioxidants
Enzymes
Superoxide Dismutase
Fibroblasts
glutathione peroxidase GPX1
Irradiation
Tissue
tert-Butylhydroperoxide
Paraquat
Mitochondria
Whole-Body Irradiation
Reperfusion Injury
Cytosol
Breeding
Animals

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. / Van Remmen, Holly; Qi, Wenbo; Sabia, Marian; Freeman, Gregory; Estlack, Larry; Yang, Hong; Guo, Zhong Mao; Huang, Ting Ting; Strong, John R; Lee, Shuko; Epstein, Charles J.; Richardson, Arlan.

In: Free Radical Biology and Medicine, Vol. 36, No. 12, 15.06.2004, p. 1625-1634.

Research output: Contribution to journalArticle

Van Remmen, H, Qi, W, Sabia, M, Freeman, G, Estlack, L, Yang, H, Guo, ZM, Huang, TT, Strong, JR, Lee, S, Epstein, CJ & 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, vol. 36, no. 12, pp. 1625-1634. https://doi.org/10.1016/j.freeradbiomed.2004.03.016
Van Remmen, Holly ; Qi, Wenbo ; Sabia, Marian ; Freeman, Gregory ; Estlack, Larry ; Yang, Hong ; Guo, Zhong Mao ; Huang, Ting Ting ; Strong, John R ; Lee, Shuko ; Epstein, Charles J. ; Richardson, Arlan. / Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. In: Free Radical Biology and Medicine. 2004 ; Vol. 36, No. 12. pp. 1625-1634.
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AU - Yang, Hong

AU - Guo, Zhong Mao

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