Gene expression profiling of NRF2-mediated protection against oxidative injury

• Published in: Free radical biology & medicine Vol. 38; no. 3; pp. 325 - 343
• Main Authors: Cho, Hye-Youn, Reddy, Sekhar P., DeBiase, Andrea, Yamamoto, Masayuki, Kleeberger, Steven R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2005
• Subjects: Animals; Antioxidant; Antioxidants - metabolism; Atmosphere Exposure Chambers; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Free radicals; Gene Expression Profiling; Hyperoxia; Hyperoxia - metabolism; Hyperoxia - pathology; Immunohistochemistry; Lung; Lung - drug effects; Lung - metabolism; Lung - pathology; Mice; Mice, Inbred ICR; Mice, Knockout; Microarray; Models, Biological; NF-E2-Related Factor 2; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxygen - toxicity; RNA, Messenger - genetics; RNA, Messenger - metabolism; Time Factors; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factor; Lung; QTL; pTyr; HO-1; Microarray; Ex; NRF2; ANOVA; Gadd45; RT-PCR; Transcription factor; GSH; EpRE; G6PD; Free radicals; DAB; HSP; GST; PKC; SOD; AOX; Antioxidant; CP; GPx; PPARγ; MMP; ARE; TXNRD; GGT; MAS5; Hyperoxia; ROS
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2004.10.013

Nuclear factor E2 p45-related factor 2 (NRF2) contributes to cellular protection against oxidative insults and chemical carcinogens via transcriptional activation of antioxidant/detoxifying enzymes. To understand the molecular basis of NRF2-mediated protection against oxidative lung injury, pulmonary gene expression profiles were characterized in Nrf2-disrupted ( Nrf2 −/−) and wild-type ( Nrf2 +/+) mice exposed to hyperoxia or air. Genes expressed constitutively higher in Nrf2 +/+ mice than in Nrf2 −/− mice included antioxidant defense enzyme and immune cell receptor genes. Higher basal expression of heat shock protein and structural genes was detected in Nrf2 −/− mice relative to Nrf2 +/+ mice. Hyperoxia enhanced expression of 175 genes (≥ twofold) and decreased expression of 100 genes (≥50%) in wild-type mice. Hyperoxia-induced upregulation of many well-known/new antioxidant/defense genes (e.g., Txnrd1, Ex, Cp-2) and other novel genes (e.g., Pkc-α, Tcf-3, Ppar-γ) was markedly greater in Nrf2 +/+ mice than in Nrf2 −/− mice. In contrast, induced expression of genes encoding extracellular matrix and cytoskeletal proteins was higher in Nrf2 −/− mice than in Nrf2 +/+ mice. These NRF2-dependent gene products might have key roles in protection against hyperoxic lung injury. Results from our global gene expression profiles provide putative downstream molecular mechanisms of oxygen tissue toxicity.