The transcription factor (TF) HIF1 is one of the most important factors of adaptation to chronic cerebral hypoxia. However, under the conditions of acute hypoxia and reoxygenation, the stress response TF (NRF2) becomes important. The interaction between these proteins at the level of regulation of antioxidant defense and glucose metabolism has been shown previously in hypoxia-sensitive cancer tumors. Here, we have studied the effect of severe hypobaric hypoxia (SH) on HIF1- and NRF2-dependent processes in the rat neocortex. We revealed the joint regulation of glutathione-dependent antioxidant systems by these proteins, which influenced the total antiradical activity and the cellular redox status. In particular, HIF1 inhibition prevented the SH-induced oxidative shift 23 h after reoxygenation, which was accompanied by an increase in the content of total glutathione and the activity of glutathione reductase. Both of these effects were NRF2-dependent, which suggests that this transcription factor is activated in response to SH in combination with HIF1 inhibition. The data confirm the previous hypothesis about the maladaptive effect of HIF1 under the conditions of acute hypoxia and reoxygenation and point to the contribution of NRF2 the protective mechanisms in the post-hypoxic period. The hypothesis of interaction between these transcription factors in the (post)hypoxic period requires further verification and may have substantial influence on understanding the molecular pathomechanisms of cerebral hypoxia.

中文翻译：

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严重缺氧对大鼠新皮层中HIF1和Nrf2介导的抗氧化防御机制的影响

转录因子（TF）HIF1是适应慢性脑缺氧的最重要因素之一。然而，在急性缺氧和复氧的条件下，应激反应TF（NRF2）变得很重要。这些蛋白质之间在抗氧化防御和葡萄糖代谢调节水平上的相互作用先前已在对缺氧敏感的癌症肿瘤中得到证实。在这里，我们研究了严重低压缺氧（SH）对大鼠新皮层中HIF1和NRF2依赖性过程的影响。我们揭示了这些蛋白对谷胱甘肽依赖性抗氧化剂系统的联合调节，这影响了总的抗自由基活性和细胞氧化还原状态。特别是HIF1的抑制作用阻止了再氧化后23 h SH诱导的氧化移位，随之而来的是谷胱甘肽总量和谷胱甘肽还原酶活性的增加。这两种作用都是NRF2依赖性的，这表明该转录因子在与SH结合HIF1抑制后被激活。数据证实了先前关于HIF1在急性缺氧和复氧条件下的适应不良作用的假设，并指出了NRF2在缺氧后保护机制中的作用。在（缺氧）后阶段这些转录因子之间相互作用的假说需要进一步验证，并且可能对理解脑缺氧的分子病理机制有重大影响。这表明该转录因子与SH结合HIF1抑制而被激活。数据证实了先前关于HIF1在急性缺氧和复氧条件下的适应不良作用的假设，并指出了NRF2在缺氧后保护机制中的作用。在（缺氧）后阶段这些转录因子之间相互作用的假说需要进一步验证，并且可能对理解脑缺氧的分子病理机制有重大影响。这表明该转录因子响应SH并结合HIF1抑制而被激活。数据证实了先前关于HIF1在急性缺氧和复氧条件下的适应不良作用的假设，并指出了NRF2在缺氧后保护机制中的作用。在（缺氧）后阶段这些转录因子之间相互作用的假说需要进一步验证，并且可能对理解脑缺氧的分子病理机制有重大影响。数据证实了先前关于HIF1在急性缺氧和复氧条件下的适应不良作用的假设，并指出了NRF2在缺氧后保护机制中的作用。在（缺氧）后阶段这些转录因子之间相互作用的假说需要进一步验证，并且可能对理解脑缺氧的分子病理机制有重大影响。数据证实了先前关于HIF1在急性缺氧和复氧条件下的适应不良作用的假设，并指出了NRF2在缺氧后保护机制中的作用。在（缺氧）后阶段这些转录因子之间相互作用的假说需要进一步验证，并且可能对理解脑缺氧的分子病理机制有重大影响。