Nrf2-dependent induction of NQO1 in mouse aortic endothelial cells overexpressing catalase.
Nrf2-dependent induction of NQO1 in mouse aortic endothelial cells overexpressing catalase.
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DOI：
10.1016/j.freeradbiomed.2011.04.020
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发表时间：
2011-07-01
影响因子：
7.4
通讯作者：
Guo, ZhongMao
中科院分区：
文献类型：
--
作者：
Lin, Xinghua;Yang, Hong;Zhou, LiChun;Guo, ZhongMao
关键词：
过氧化氢酶的过表达已被证明可以加速小鼠主动脉内皮细胞（MAECs）中苯并（a）芘（BaP）的解毒。NAD（P）H：醌氧化还原酶1（NQO 1）是一种催化BaP-醌解毒的酶。芳香烃受体（AhR）和核因子红细胞2相关因子-2（Nrf 2）是控制NQO 1表达的转录因子。在这里，我们研究了过氧化氢酶过表达对NQO 1，Nrf 2和AhR表达的影响。NQO 1 mRNA和蛋白质的水平在从过表达人过氧化氢酶（hCatTg）的野生型和转基因小鼠分离的MAEC中是相当的。BaP处理增加了两组中NQO 1 mRNA和蛋白水平，hCatTg MAECs中的诱导作用显著高于野生型细胞。BaP诱导的NQO 1启动子活性在hCatTg MAECs中显著高于野生型细胞。我们的数据还表明，AhR的基础水平和BaP诱导的Nrf 2水平在hCatTg MAECs中显著高于野生型细胞。特异性蛋白-1（Sp1）结合到AhR启动子区域的光神霉素A的抑制逆转了过氧化氢酶过表达对AhR表达的增强作用。通过RNA干扰敲低AhR减少了BaP诱导的Nrf 2和NQO 1的表达。敲除Nrf 2显著降低了有或无BaP处理的细胞中NQO 1 mRNA和蛋白水平。NQO 1启动子活性被废除的Nrf 2结合位点在这个启动子的突变。相反，在NQO 1启动子中AhR结合位点的突变不影响启动子活性。这些结果表明过氧化氢酶过表达通过增强Sp1-AhR-Nrf 2信号级联上调BaP诱导的NQO 1表达。
Overexpression of catalase has been shown to accelerate benzo(a)pyrene (BaP) detoxification in mouse aortic endothelial cells (MAECs ). NAD(P)H:quinone oxidoreductase1 (NQO1) is an enzyme that catalyzes BaP-quinone detoxification. Aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor-2 (Nrf2) are transcription factors that control NQO1 expression. Here, we investigated the effect of catalase overexpression on NQO1, Nrf2 and AhR expressions. The levels of NQO1 mRNA and protein were comparable in MAECs isolated from wild-type and transgenic mice that overexpress human catalase (hCatTg). BaP treatment increased NQO1 mRNA and protein levels in both groups, with a significantly greater induction in hCatTg MAECs than in wild-type cells. BaP-induced NQO1 promoter activity was dramatically higher in hCatTg MAECs than in wild-type cells. Our data also showed that the basal level of AhR and the BaP-induced level of Nrf2 were significantly higher in hCatTg MAECs than in wild-type cells. Inhibition of specificity protein-1 (Sp1) binding to the AhR promoter region by mithramycin A reversed the enhanced effect of catalase overexpression on AhR expression. Knockdown of AhR by RNA interference diminished BaP-induced expression of Nrf2 and NQO1. Knockdown of Nrf2 significantly decreased NQO1 mRNA and protein levels in cells with or without BaP treatment. NQO1 promoter activity was abrogated by mutation of the Nrf2-binding site in this promoter. In contrast, mutation of the AhR-binding site in NQO1 promoter did not affect the promoter activity. These results suggest that catalase overexpression upregulates BaP-induced NQO1 expression via enhancing the Sp1-AhR-Nrf2 signaling cascade.
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影响因子：
3.1
作者：
Fitzgerald, CT;Nebert, DW;Puga, A
通讯作者：
Puga, A
影响因子：
2.9
作者：
JAISWAL, AK
通讯作者：
JAISWAL, AK
影响因子：
4.1
作者：
Penning, TM;Ohnishi, ST;Harvey, RG
通讯作者：
Harvey, RG
DOI：
10.1073/pnas.91.18.8413
发表时间：
1994-08-30
影响因子：
11.1
作者：
JOSEPH, P;JAISWAL, AK
通讯作者：
JAISWAL, AK
影响因子：
7.4
作者：
Onumah, Ogbeyalu E.;Jules, George E.;Zhao, Yanfeng;Zhou, LiChun;Yang, Hong;Guo, ZhongMao
通讯作者：
Guo, ZhongMao