The in vivo gene expression signature of oxidative stress
The in vivo gene expression signature of oxidative stress
复制标题
DOI：
10.1152/physiolgenomics.00239.2007
复制
发表时间：
2008-06-12
影响因子：
4.6
通讯作者：
Richardson, Arlan
中科院分区：
文献类型：
--
作者：
Han, Eun-Soo;Muller, Florian L.;Richardson, Arlan
高等生物如何在体内对升高的氧化应激反应知之甚少。因此，我们测量了氧化应激参数和基因表达的改变（Affyestrium阵列）引起的活性氧升高在体内诱导敌草快或基因消融的主要抗氧化酶铜锌超氧化物歧化酶（SOD 1）和谷胱甘肽过氧化物酶-1（GPX 1）。敌草快（50 mg/kg）处理导致野生型小鼠在3-6 h内氧化损伤显著增加，但无任何致死性。相比之下，用相似浓度的敌草快处理Sod 1（-/-）或Gpx 1（-/-）小鼠，在处理1小时内导致氧化损伤显著增加，并且是致命的，即，这些小鼠对敌草快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不涉及经典抗氧化剂基因的上调，尽管Sod 1（-/-）小鼠中的长期氧化应激导致硫醇抗氧化剂的显著上调（例如，Mt 1，Srxn 1，Gclc，Txnrd 1），这似乎是由氧化还原敏感性转录因子Nrf 2介导的。我们研究的主要发现是，在野生型、Gpx 1（-/-）和Sod 1（-/-）小鼠以及未治疗的Sod 1（-/-）小鼠中，敌草快治疗对氧化应激升高的共同反应是p53靶基因（p21、Gdf 15、Plk 3、Atf 3、Trp 53 inp 1、Ddit 4、Gadd 45 a、Btg 2、Ndrg 1）的上调。回顾性比较与以往的研究表明，这些p53靶基因的诱导是一个保守的表达反应氧化应激，在体内和体外，在不同的物种和不同的细胞/器官。
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.