The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1.
The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1.
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DOI：
10.1091/mbc.e09-12-1003
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发表时间：
2010-06-15
影响因子：
3.3
通讯作者：
Görlach A
中科院分区：
文献类型：
--
作者：
Diebold I;Petry A;Hess J;Görlach A
NADPH 氧化酶产生活性氧 (ROS)。我们研究了 NOX4 在缺氧条件下的作用。由于 HIF-1α 结合和 NOX4 启动子激活，缺氧增强了肺平滑肌细胞和肺组织中 NOX4 的表达。 HIF-1α 依赖的 NOX4 诱导恢复了缺氧后的 ROS 水平，并通过缺氧诱导增殖。参考列表中未引用以下引文，或者参考/引文的样式不正确：。 NADPH 氧化酶是活性氧 (ROS) 的重要来源，可能导致与增殖增强相关的各种疾病。 NOX4 似乎参与血管信号传导，并可能有助于对缺氧的反应。然而，缺氧条件下控制 NOX4 水平的确切机制尚未解决。我们发现，缺氧会迅速增强肺动脉平滑肌细胞 (PASMC) 以及缺氧小鼠肺血管中的 NOX4 mRNA 和蛋白水平。这种反应依赖于缺氧诱导的转录因子 HIF-1α，因为 HIF-1α 的过度表达会增加 NOX4 的表达，而 HIF-1α 的缺失会阻止这种反应。 NOX4 启动子中假定的缺氧反应元件的突变消除了缺氧和 HIF-1α 诱导的 NOX4 启动子激活。染色质免疫沉淀证实 HIF-1α 与 NOX4 基因结合。 HIF-1α 诱导 NOX4 有助于维持缺氧后的 ROS 水平以及缺氧诱导的 PASMC 增殖。这些发现表明NOX4是参与缺氧反应的HIF-1α的新靶基因。与我们之前发现的 NOX4 在常氧条件下介导 HIF-1α 诱导的发现一起，这些数据表明 NOX4 和 HIF-1α 之间的信号轴在缺氧和非缺氧条件下的各种心血管疾病中发挥着重要作用。
NADPH oxidases generate reactive oxygen species (ROS). We studied the role of NOX4 under hypoxia. Hypoxia enhanced NOX4 expression in lung smooth-muscle cells and lung tissue due to HIF-1α binding and activation of the NOX4 promoter. HIF-1α–dependent NOX4 induction restored ROS levels after hypoxia and induced proliferation by hypoxia. The following citations were not referenced in the reference list or the reference/citation is not styled correctly:. NADPH oxidases are important sources of reactive oxygen species (ROS), possibly contributing to various disorders associated with enhanced proliferation. NOX4 appears to be involved in vascular signaling and may contribute to the response to hypoxia. However, the exact mechanisms controlling NOX4 levels under hypoxia are not resolved. We found that hypoxia rapidly enhanced NOX4 mRNA and protein levels in pulmonary artery smooth-muscle cells (PASMCs) as well as in pulmonary vessels from mice exposed to hypoxia. This response was dependent on the hypoxia-inducible transcription factor HIF-1α because overexpression of HIF-1α increased NOX4 expression, whereas HIF-1α depletion prevented this response. Mutation of a putative hypoxia-responsive element in the NOX4 promoter abolished hypoxic and HIF-1α–induced activation of the NOX4 promoter. Chromatin immunoprecipitation confirmed HIF-1α binding to the NOX4 gene. Induction of NOX4 by HIF-1α contributed to maintain ROS levels after hypoxia and hypoxia-induced proliferation of PASMCs. These findings show that NOX4 is a new target gene of HIF-1α involved in the response to hypoxia. Together with our previous findings that NOX4 mediates HIF-1α induction under normoxia, these data suggest an important role of the signaling axis between NOX4 and HIF-1α in various cardiovascular disorders under hypoxic and also nonhypoxic conditions.