Gene expression profiling of NRF2-mediated protection against oxidative injury
Gene expression profiling of NRF2-mediated protection against oxidative injury
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DOI：
10.1016/j.freeradbiomed.2004.10.013
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发表时间：
2005-02-01
影响因子：
7.4
通讯作者：
Kleeberger, SR
中科院分区：
文献类型：
--
作者：
Cho, HY;Reddy, SP;Kleeberger, SR
核因子E2 p45相关因子2（NRF 2）通过抗氧化/解毒酶的转录激活而有助于细胞保护免受氧化损伤和化学致癌物。为了了解NRF 2介导的抗氧化性肺损伤保护的分子基础，在暴露于高氧或空气的Nrf 2破坏（Nrf 2（-/-））和野生型（Nrf 2（-/-））小鼠中表征肺基因表达谱。在Nrf 2（+/+）小鼠中组成性表达高于Nrf 2（-/-）小鼠的基因包括抗氧化防御酶和免疫细胞受体基因。相对于Nrf 2（+/+）小鼠，在Nrf 2（-/-）小鼠中检测到更高的热休克蛋白和结构基因的基础表达。在野生型小鼠中，高氧增加了175个基因的表达（大于或等于两倍），减少了100个基因的表达（大于或等于50%）。高氧诱导的许多已知/新的抗氧化剂/防御基因（例如Txnrd 1、Ex、Cp-2）和其他新基因（例如，PKC-α、Tcf-3、Ppar-gamma）在Nrf 2（+/+）小鼠中显著高于Nrf 2（-/-）小鼠。相比之下，Nrf 2（-/-）小鼠中编码细胞外基质和细胞骨架蛋白的基因的诱导表达高于Nrf 2（+/+）小鼠。这些NRF 2依赖的基因产物可能在抗高氧肺损伤中起关键作用。从我们的全球基因表达谱的结果提供了推定的下游分子机制的氧组织毒性。(C)2004年爱思唯尔公司All rights reserved.
Nuclear factor E2 p45-related factor 2 (NRF2) contributes to cellular protection against oxidative insults and chemical carcinogens via transcriptional activation of anitioxidant/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 (greater than or equal to twofold) and decreased expression of 100 genes (greater than or equal to50%) in wild-type mice. Hyperoxia-induced upregulation of many well-known/new antioxidant/defense genes (e.g. Txnrd 1, Ex, Cp-2) and other novel genes (e.g., Pkc-alpha, Tcf-3, Ppar-gamma) 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. (C) 2004 Elsevier Inc. All rights reserved.