KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells
KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells
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DOI：
10.1161/atvbaha.108.165811
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发表时间：
2008-07-01
影响因子：
8.7
通讯作者：
Horrevoets, Anton J. G.
中科院分区：
文献类型：
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作者：
Fledderus, Joost O.;Boon, Reinier A.;Horrevoets, Anton J. G.
抗动脉粥样硬化血流诱导抗炎Kruppel样因子2（KLF 2）的表达，并激活血管内皮细胞中的抗氧化转录因子核因子红细胞2相关因子2（Nrf 2）。以前，我们获得了KLF 2诱导的基因表达谱的EC中，含有几个Nrf 2靶基因。我们的目的是研究KLF 2在剪切应力介导的人脐静脉内皮细胞（HUVECs）中Nrf 2活化中的作用。方法和结果-剪切和KLF 2升高了Nrf 2及其靶点NAD（P）H脱氢酶醌1（NQO 1）和血红素加氧酶（HO-1）的表达。KLF 2敲低表明剪切诱导的NQO 1表达依赖于KLF 2，而Nrf 2不依赖于KLF 2。KLF 2过表达在缺乏流动导致更有效的激活Nrf 2的叔丁基对苯二酚（tBHQ）通过增强核定位，并促进了一个大面板的Nrf 2依赖性基因的表达，从而产生上级保护氧化应激。剪切，KLF 2，和Nrf 2诱导的转录组的比较表明，大多数剪切调制的基因集的影响KLF 2或Nrf2.Conclusions，我们报告，KLF 2大大提高抗氧化活性的Nrf 2通过增加其核定位和激活。这两种转录因子的协同活性对内皮细胞中剪切应力诱导的转录组形成了主要贡献。
Objective-Atheroprotective blood flow induces expression of anti-inflammatory Kruppel-like factor 2 (KLF2) and activates antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in vascular endothelium. Previously, we obtained KLF2-induced gene expression profiles in ECs, containing several Nrf2 target genes. Our aim was to investigate the role of KLF2 in shear stress-mediated activation of Nrf2 in human umbilical vein endothelial cells (HUVECs).Methods and Results-Expression of Nrf2 and its targets NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase (HO-1) was elevated by shear and KLF2. KLF2 knockdown showed that shear-induced expression of NQO1 but not Nrf2 was dependent on KLF2. KLF2 overexpression in absence of flow resulted in more efficient activation of Nrf2 by tert-butyl hydroquinone (tBHQ) through enhanced nuclear localization, and promoted expression of a large panel of Nrf2-dependent genes resulting in superior protection against oxidative stress. Comparison of shear-, KLF2-, and Nrf2-induced transcriptomes showed that the majority of shear-modulated gene sets is influenced by KLF2 or Nrf2.Conclusions-We report that KLF2 substantially enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation. The synergistic activity of these two transcription factors forms a major contribution to the shear stress-elicited transcriptome in endothelial cells.