The in vivo gene expression signature of oxidative stress.
How higher organisms respond to elevated oxidative stress in vivo is poorly understood. Therefore, we measured oxidative stress parameters and gene expression alterations (Affymetrix arrays) in the liver caused by elevated reactive oxygen species induced in vivo by diquat or by genetic ablation of the major antioxidant enzymes CuZn-superoxide dismutase (Sod1) and glutathione peroxidase-1 (Gpx1). Diquat (50 mg/kg) treatment resulted in a significant increase in oxidative damage within 3-6 h in wild-type mice without any lethality. In contrast, treatment of Sod1(-/-) or Gpx1(-/-) mice with a similar concentration of diquat resulted in a significant increase in oxidative damage within an hour of treatment and was lethal, i.e., these mice are extremely sensitive to the oxidative stress generated by diquat. The expression response to elevated oxidative stress in vivo does not involve an upregulation of classic antioxidant genes, although long-term oxidative stress in Sod1(-/-) mice leads to a significant upregulation of thiol antioxidants (e.g., Mt1, Srxn1, Gclc, Txnrd1), which appears to be mediated by the redox-sensitive transcription factor Nrf2. The main finding of our study is that the common response to elevated oxidative stress with diquat treatment in wild-type, Gpx1(-/-), and Sod1(-/-) mice and in untreated Sod1(-/-) mice is an upregulation of p53 target genes (p21, Gdf15, Plk3, Atf3, Trp53inp1, Ddit4, Gadd45a, Btg2, Ndrg1). A retrospective comparison with previous studies shows that induction of these p53 target genes is a conserved expression response to oxidative stress, in vivo and in vitro, in different species and different cells/organs.
Han
Eun-Soo
ES
Department of Biological Science, University of Tulsa, Tulsa, Oklahoma, USA.
Muller
Florian L
FL
Pérez
Viviana I
VI
Qi
Wenbo
W
Liang
Huiyun
H
Xi
Liang
L
Fu
Chunxiao
C
Doyle
Erin
E
Hickey
Morgen
M
Cornell
John
J
Epstein
Charles J
CJ
Roberts
L Jackson
LJ
Van Remmen
Holly
H
Richardson
Arlan
A
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004178:Diquat / Q000633:toxicity; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000172:deficiency; D015227:Lipid Peroxidation / Q000187:drug effects; D008107:Liver Diseases / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013482:Superoxide Dismutase / Q000172:deficiency; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004247:DNA; D004178:Diquat; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse