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首页> 外文期刊>Functional & integrative genomics >Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia
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Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia

机译：短期低压低氧条件下大鼠脑转录因子NRF2介导的氧化应激反应途径的上调

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Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p < 0.05, <1.5-fold) after 0.5, 1, 3, 6, and 12 h of hypoxia, respectively. Biological processes like regulation, metabolic, and transport pathways are temporally activated along with anti- and proinflammatory signaling networks like PI3K/AKT, NF-κB, ERK/MAPK, IL-6 and IL-8 signaling. Irrespective of exposure durations, nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated oxidative stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.
机译：暴露于高海拔地区（从而导致低压缺氧）会诱发大脑中的电生理，代谢和形态学改变，从而导致几种神经系统临床综合症。尽管已知缺氧发作是许多神经病理学的常见因素，但是关于潜在的细胞和分子机制的信息却很少。在这项研究中，我们调查了短期（0-12小时）慢性低压缺氧对大鼠脑整体基因表达的时间影响，然后进行详细的经典途径分析和调节网络鉴定。我们的分析显示，分别在缺氧0.5、1、3、6和12 h后33、17、53、81和296个基因发生了显着变化（p <0.05，<1.5倍）。诸如调节，代谢和运输途径等生物过程与诸如PI3K / AKT，NF-κB，ERK / MAPK，IL-6和IL-8信号传导的抗炎和促炎性信号传导网络在时间上被激活。不论暴露时间长短，在所有时间点都检测到核因子（类胡萝卜素衍生的2）样2（NRF2）介导的氧化应激反应途径和基因，表明NRF2-ARE抗氧化防御系统的激活。通过定量RT-PCR和western blot评估颞和脑区域所选基因的表达水平，进一步验证了结果。总而言之，我们的全脑方法在低压缺氧期间对基因表达模式进行时间监控，导致（1）解释了在缺氧发作期间激活的通路和信号网络的序列，以及（2）阐明了NRF2精心设计的抗氧化剂反应内在防御机制。这项研究的结果将有助于更好地理解和处理由缺氧引起的脑部疾病。

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