BRG1 regulates NOX gene transcription in endothelial cells and contributes to cardiac ischemia-reperfusion injury
BRG1 regulates NOX gene transcription in endothelial cells and contributes to cardiac ischemia-reperfusion injury
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BRG1调节内皮细胞NOX基因转录并导致心脏缺血再灌注损伤
DOI：
10.1016/j.bbadis.2018.08.002
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发表时间：
2018-10-01
影响因子：
6.2
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Li, Zilong;Zhang, Xinjian;Xu, Yong
活性氧（ROS）的过度积累被认为是许多心血管疾病的罪魁祸首。在血管内皮细胞中，ROS的产生是由NAPDH氧化酶（NOX）介导的。在本研究中，我们研究了染色质重塑蛋白BRG 1在NOX反式激活中的作用以及其在心肌缺血再灌注损伤中的意义。我们报告说，在响应缺氧-复氧（HR）BRG 1被招募到NOX启动子区在永生化内皮细胞和原代微血管内皮细胞。BRG 1敲低减弱了HR刺激对NOX基因的诱导。BRG 1沉默对NOX反式激活的抑制被活性组蛋白修饰（组蛋白H3和H4的乙酰化）的丧失和NOX启动子周围抑制性组蛋白修饰（组蛋白H3 K9的二甲基化）的重新出现所抵消。有趣的是，H3 K9脱甲基酶KDM 3A以与BRG 1相似的动力学结合到NOX启动子，并与BRG 1相互作用以激活NOX转录。KDM 3A耗竭改善了暴露于HR的内皮细胞中的NOX诱导和ROS产生。最后，内皮特异性BRG 1缺失的小鼠免受心脏缺血再灌注损伤。总之，我们的数据表明，BRG 1可能链接表观遗传激活的NOX转录内皮细胞心肌缺血再灌注损伤。
Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for a host of cardiovascular diseases. In vascular endothelial cells, ROS production is mediated by NAPDH oxidases (NOX). In the present study we investigated the role of the chromatin remodeling protein BRG1 in NOX trans-activation as well as its implication in cardiac ischemia-reperfusion injury. We report that in response to hypoxia-reoxygenation (HR) BRG1 was recruited to the NOX promoter regions in both immortalized endothelial cells and primary microvascular endothelial cells. BRG1 knockdown attenuated the induction of NOX genes by HR stimulation. Suppression of NOX trans-activation by BRG1 silencing was paralleled by the loss of active histone modifications (acetylation of histones H3 and H4) and the re-appearance of repressive histone modification (dimethylation of histone H3K9) surrounding the NOX promoter. Of interest, the H3K9 demethylase KDM3A bound to the NOX promoters with kinetics similar to BRG1 and interacted with BRG1 to activate NOX transcription. KDM3A depletion ameliorated NOX induction and ROS production in endothelial cells exposed to HR. Finally, mice with endothelial-specific deletion of BRG1 were protected from cardiac ischemia-reperfusion injury. In conclusion, our data suggest that BRG1 may link epigenetic activation of NOX transcription in endothelial cells to cardiac ischemia reperfusion injury.