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 gamma 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 gamma 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.
Van Remmen
Holly
H
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284-7762, USA. vanremmen@uthscsa.edu
Qi
Wenbo
W
Sabia
Marian
M
Freeman
Gregory
G
Estlack
Larry
L
Yang
Hong
H
Mao Guo
Zhong
Z
Huang
Ting-Ting
TT
Strong
Randy
R
Lee
Shuko
S
Epstein
Charles J
CJ
Richardson
Arlan
A
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001835:Body Weight; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D017202:Myocardial Ischemia; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D015427:Reperfusion Injury; D012867:Skin / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D013997:Time Factors
D000975:Antioxidants; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D010269:Paraquat