The in vivo gene expression signature of oxidative stress

Eun Soo Han, Florian L. Muller, Viviana I. Pérez, Wenbo Qi, Huiyun Liang, Liang Xi, Chunxiao Fu, Erin Doyle, Morgen Hickey, John Cornell, Charles J. Epstein, L. Jackson Roberts, Holly Van Remmen, Arlan Richardson

Research output: Contribution to journalArticle

162 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)112-126
Number of pages15
JournalPhysiological Genomics
Volume34
Issue number1
DOIs
StatePublished - Jun 2008

Keywords

  • Gene expression
  • Gpx1
  • Oxidative stress
  • Sod1
  • p53 target genes

ASJC Scopus subject areas

  • Physiology
  • Genetics

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    Han, E. S., Muller, F. L., Pérez, V. I., Qi, W., Liang, H., Xi, L., Fu, C., Doyle, E., Hickey, M., Cornell, J., Epstein, C. J., Roberts, L. J., Van Remmen, H., & Richardson, A. (2008). The in vivo gene expression signature of oxidative stress. Physiological Genomics, 34(1), 112-126. https://doi.org/10.1152/physiolgenomics.00239.2007