Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis.
Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis.
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缺氧诱导因子 1α 和 2α 之间的相互拮抗调节氧传感和心肺稳态。
DOI：
10.1073/pnas.1305961110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Prabhakar,NanduriR
中科院分区：
文献类型：
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作者：
Yuan,Guoxiang;Peng,Ying-Jie;Reddy,VaddiDamodara;Makarenko,VladislavV;Nanduri,Jayasri;Khan,ShakilA;Garcia,JosephA;Kumar,GaneshK;Semenza,GreggL;Prabhakar,NanduriR
呼吸和血压处于持续的稳态调节下，以维持向组织的最佳氧气输送。由颈动脉体引发的化学感应反射和肾上腺髓质分泌的儿茶酚胺是维持呼吸和心血管稳态的主要机制；然而，潜在的分子机制尚不清楚。在这里，我们报告说，缺氧诱导因子 1 (HIF-1) 和 HIF-2 的平衡活性对于颈动脉体和肾上腺髓质的氧传感及其对心肺功能的控制至关重要。在Hif2α+/-小鼠中，部分HIF-2α缺乏会增加HIF-1α和NADPH氧化酶2的水平，导致细胞内氧化还原状态氧化、缺氧敏感性增强和心肺异常，而用HIF-1α抑制剂或超氧阴离子清除剂治疗可以逆转这些情况。相反，在 Hif1α+/- 小鼠中，部分 HIF-1α 缺乏会增加 HIF-2α 和超氧化物歧化酶 2 的水平，导致细胞内氧化还原状态降低、氧感应减弱、颈动脉体和对慢性缺氧的通气反应受损，这些可通过 HIF-2α 抑制剂治疗来纠正。在 Hif1α+/- 小鼠或 Hif2α+/- 小鼠中观察到的异常在 Hif1α+/- ；Hif2α+/- 小鼠中未观察到。这些观察结果表明，氧化还原平衡是由 HIF-α 同种型之间的相互拮抗决定的，它确定了颈动脉体和肾上腺髓质缺氧感知的设定点，并且是维持心肺稳态所必需的。
Breathing and blood pressure are under constant homeostatic regulation to maintain optimal oxygen delivery to the tissues. Chemosensory reflexes initiated by the carotid body and catecholamine secretion from the adrenal medulla are the principal mechanisms for maintaining respiratory and cardiovascular homeostasis; however, the underlying molecular mechanisms are not known. Here, we report that balanced activity of hypoxia-inducible factor-1 (HIF-1) and HIF-2 is critical for oxygen sensing by the carotid body and adrenal medulla, and for their control of cardio-respiratory function. InHif2α+/−mice, partial HIF-2α deficiency increased levels of HIF-1α and NADPH oxidase 2, leading to an oxidized intracellular redox state, exaggerated hypoxic sensitivity, and cardio-respiratory abnormalities, which were reversed by treatment with a HIF-1α inhibitor or a superoxide anion scavenger. Conversely, inHif1α+/−mice, partial HIF-1α deficiency increased levels of HIF-2α and superoxide dismutase 2, leading to a reduced intracellular redox state, blunted oxygen sensing, and impaired carotid body and ventilatory responses to chronic hypoxia, which were corrected by treatment with a HIF-2α inhibitor. None of the abnormalities observed inHif1α+/−mice orHif2α+/−mice were observed inHif1α+/−;Hif2α+/−mice. These observations demonstrate that redox balance, which is determined by mutual antagonism between HIF-α isoforms, establishes the set point for hypoxic sensing by the carotid body and adrenal medulla, and is required for maintenance of cardio-respiratory homeostasis.