Han Eun-Soo, Muller Florian L, Pérez Viviana I, Qi Wenbo, Liang Huiyun, Xi Liang, Fu Chunxiao, Doyle Erin, Hickey Morgen, Cornell John, Epstein Charles J, Roberts L Jackson, Van Remmen Holly, Richardson Arlan
Department of Biological Science, University of Tulsa, Tulsa, Oklahoma, USA.
Physiol Genomics. 2008 Jun 12;34(1):112-26. doi: 10.1152/physiolgenomics.00239.2007. Epub 2008 Apr 29.
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.
高等生物在体内如何应对升高的氧化应激尚不清楚。因此，我们测量了由百草枯在体内诱导产生的活性氧增加或主要抗氧化酶铜锌超氧化物歧化酶（Sod1）和谷胱甘肽过氧化物酶-1（Gpx1）基因敲除所导致的肝脏中的氧化应激参数和基因表达变化（Affymetrix芯片）。百草枯（50 mg/kg）处理在3至6小时内导致野生型小鼠体内氧化损伤显著增加，且无任何致死性。相比之下，用相似浓度的百草枯处理Sod1（-/-）或Gpx1（-/-）小鼠，在处理后一小时内氧化损伤就显著增加且具有致死性，即这些小鼠对百草枯产生的氧化应激极其敏感。体内对升高的氧化应激的表达反应并不涉及经典抗氧化基因的上调，尽管Sod1（-/-）小鼠中的长期氧化应激导致硫醇抗氧化剂（如Mt1、Srxn1、Gclc、Txnrd1）显著上调，这似乎是由氧化还原敏感转录因子Nrf2介导的。我们研究的主要发现是，野生型、Gpx1（-/-）和Sod1（-/-）小鼠以及未处理的Sod1（-/-）小鼠在百草枯处理后对升高的氧化应激的共同反应是p53靶基因（p21、Gdf15、Plk3、Atf3、Trp53inp1、Ddit4、Gadd45a、Btg2、Ndrg1）的上调。与先前研究的回顾性比较表明，这些p53靶基因的诱导是在体内和体外、不同物种以及不同细胞/器官中对氧化应激的一种保守表达反应。
