EPAS1/HIF-2α: a key regulator for chronic hypoxia across species.
EPAS1/HIF-2α: a key regulator for chronic hypoxia across species.
复制标题
DOI：
10.1113/jp283554
复制
发表时间：
2022-09
影响因子：
5.5
通讯作者：
Moya, Esteban A.
中科院分区：
文献类型：
--
作者：
Moya, Esteban A.
短暂或长时间暴露于缺氧的个体表现出旨在维持氧稳态的生理变化。例如，急性暴露于缺氧由于颈动脉体的外周化学感受器的激活以及缺氧触发的心率变化而产生缺氧缓解反应（HVR）。长时间缺氧（慢性持续性缺氧）导致不同的反应，包括通气的继发性增加，称为缺氧适应性习服（VAH），颈动脉体的扩大，涉及啮齿动物模型和人类遗传研究的实验描述了EPAS 1/HIF-2α通路作为这些缺氧诱导后果的主要触发因素之一的重要性（Yu et al. 2022; Hodson et al. 2016），支持EPAS 1/HIF-2α通路对缺氧适应机制至关重要的观点。例如，HIF-2α的药理学抑制和在敲除小鼠中进行的实验表明，HIF-2α的破坏导致暴露于缺氧数天后VAH变钝。对生活在高海拔地区的人群的研究表明，参与EPAS 1/HIF-2α通路的基因显示出选择的迹象，并与高海拔地区相对较低的血红蛋白水平相关，即与海平面的个体相似，但与其他高海拔人群（如安第斯山脉）相比，血红蛋白水平较低。此外，与安第斯山脉高海拔地区的人群相比，高海拔地区的藏人表现出更强的通风能力。在许多情况下，这些缺氧引起的变化的潜在适应或适应不良的作用仍然未知，许多研究小组正在积极应用新的方法来回答这些问题。
Individuals exposed to hypoxia for brief or long periods of time manifest physiological changes that aim to maintain oxygen homeostasis. For example, acute exposure to hypoxia produces hypoxic ventilatory response (HVR) due to activation of the peripheral chemoreceptors of the carotid body, as well as hypoxia-triggered changes in heart rate. Exposure to extended periods of hypoxia (chronic sustained hypoxia) results in different responses, including a secondary increase in ventilation termed ventilatory acclimatization to hypoxia (VAH), enlargement of carotid bodies, and increased hemoglobin concentration.Experiments involving rodent models and human genetic studies describe the importance of the EPAS1/HIF-2α pathway as one of the main triggers of these hypoxia-induced consequences (Yu et al. 2022; Hodson et al. 2016), supporting the idea that the EPAS1/HIF-2α pathway is crucial for mechanisms of hypoxia adaptation. For instance, pharmacological inhibition of HIF-2α and experiments performed in knockout mice show that disruption of HIF-2α results in a blunted VAH after days of exposure to hypoxia. Studies of human populations living at high altitude demonstrate that genes involved in the EPAS1/HIF-2α pathway show signs of selection and are associated with relatively lower levels of hemoglobin at high altitude, ie, similar to individuals at sea level but lower when compared to other high-altitude populations such as Andeans. And also, Tibetans at highaltitude show increased ventilation when compared to Andean high-altitude populations. In many cases, the potential adaptive or maladaptive roles of these hypoxia-induced changes remain unknown and many groups are enthusiastically applying novel approaches to answer these questions.