Laminar flow induction of antioxidant response element-mediated genes in endothelial cells - A novel anti-inflammatory mechanism
Laminar flow induction of antioxidant response element-mediated genes in endothelial cells - A novel anti-inflammatory mechanism
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DOI：
10.1074/jbc.m203161200
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发表时间：
2003-01-10
影响因子：
4.8
通讯作者：
Kunsch, C
中科院分区：
文献类型：
--
作者：
Chen, XL;Varner, SE;Kunsch, C
动脉粥样硬化病变优先发生在暴露于非层流和低流体切应力的血管系统区域，而层流和高流体切应力则具有动脉粥样硬化保护作用。我们已经鉴定了一组基因，包括NAD（P）H：醌氧化还原酶-1（NQO 1）、血红素加氧酶-1（HO-1）、铁蛋白（重链和轻链）、微粒体环氧化物水解酶、谷胱甘肽S-转移酶和γ-谷氨酰半胱氨酸合酶，其表达是通过在内皮细胞（EC）中暴露于长期生理水平的稳定层流（剪切应力= 20 dyn/cm（2））诱导的。这些基因在其启动子中含有抗氧化反应元件（ARE）或ARE样转录调控序列，通常起保护细胞免受氧化应激的作用。我们证明，EC暴露于层流激活ARE介导的转录活性。从NQO 1或HO-1启动子的ARE突变废除层流诱导的NQO 1和HO-1转录激活。反义Nrf 2（ARE的转录因子），显性负Nrf 2，或Nrf 2的胞质抑制剂（Keap 1/INrf 2）的表达抑制EC层流诱导的NQO 1启动子激活。此外，NQO 1或Nrf 2的表达抑制肿瘤坏死因子-α诱导的EC中VCAM-1（血管细胞粘附分子-1）基因表达的激活。这些数据定义ARE作为一种新的内皮剪切应力响应元件。此外，通过ARE依赖性转录机制的抗氧化基因的层流激活可能代表了血管系统中新的动脉粥样硬化保护和抗炎机制。
Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and gamma-glutamyleysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm(2)) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-alpha-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature.