Enhanced leukocyte HIF-1α and HIF-1 DNA binding in humans after rapid ascent to 4300 m
Enhanced leukocyte HIF-1α and HIF-1 DNA binding in humans after rapid ascent to 4300 m
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DOI：
10.1016/j.freeradbiomed.2009.03.009
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发表时间：
2009-06-01
影响因子：
7.4
通讯作者：
Honigman, Benjamin
中科院分区：
文献类型：
--
作者：
van Patot, Martha C. Tissot;Serkova, Natalie J.;Honigman, Benjamin
缺氧在癌症、糖尿病、心血管疾病、中风、肺部疾病、炎症、器官移植和伤口愈合等多种疾病和临床条件的发病机制中起着至关重要的作用。低氧诱导转录因子（hypoxia-inducible transcription factor， HIF）在疾病发展中的作用研究，其基本前提是HIF在人体缺氧时在体内被激活，但这一基本生理学前提从未得到证实。因此，我们假设HIF-1 DNA结合会在人类体内对急性全身缺氧做出反应而增强。14名受试者在低压缺氧舱中暴露于常氧（1600米）和低氧（4300米，约12% O-2）下（8小时）。在循环白细胞中评估HIF-1 DNA结合和HIF-1 α蛋白。氧化标志物通过核磁共振血浆代谢组学和尿15- f -2t-异前列腺素浓度进行评估。白细胞HIF-1 DNA结合增加（p=0.007），低氧时HIF-1 α比常氧时高。循环总谷胱甘肽减少35% (p=0.001)，抗乳酸和琥珀酸分别增加29%和158% (p=0.007和0.001)，尿15- f -2t-异前列腺素也增加（p=0.037）。暴露于12%氧的健康人白细胞中HIF-1 DNA结合和HIF-1 α在体内升高，与血浆和尿中缺氧应激标志物相关。(C) 2009爱思唯尔公司版权所有。
Hypoxia plays a crucial role in the pathogenesis of a multitude of diseases and clinical conditions such as cancer, diabetes, cardiovascular disease, stroke, pulmonary disease, inflammation, organ transplant, and wound healing. Investigations into the role of hypoxia-inducible transcription factor (HIF) in disease development have been conducted with the basic premise that HIF is activated in vivo during hypoxia in humans, yet this basic physiologic premise has never verified. Thus, we hypothesized that HIF-1 DNA binding would be enhanced in vivo in humans in response to acute global hypoxia. Fourteen human subjects were exposed to normoxia (1600 m) and hypoxia (4300 m, approximate to 12% O-2) in a hypobaric hypoxic chamber (8 h). HIF-1 DNA binding and HIF-1 alpha protein were evaluated in circulating leukocytes. Oxidative markers were evaluated by plasma metabolomics using nuclear magnetic resonance and by urinary 15-F-2t-isoprostane concentrations. Leukocyte HIF-1 DNA binding was increased (p=0.007) and HIF-1 alpha was greater during hypoxia compared to normoxia. Circulating total glutathione was reduced by 35% (p=0.001), anti lactate and succinate were increased by 29 and 158%, respectively (p=0.007 and 0.001), as were urinary 15-F-2t-isoprostanes (p=0.037). HIF-1 DNA binding and HIF-1 alpha, were elevated in vivo in leukocytes of healthy human Subjects exposed to 12% oxygen, in association with plasma and urinary markers of hypoxic stress. (C) 2009 Elsevier Inc. All rights reserved.