Regulation of carotid body oxygen sensing by hypoxia-inducible factors.
Regulation of carotid body oxygen sensing by hypoxia-inducible factors.
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DOI：
10.1007/s00424-015-1719-z
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Semenza GL
中科院分区：
文献类型：
--
作者：
Prabhakar NR;Semenza GL
颈动脉小体及其化学感觉反射对呼吸和血压的动态平衡调节至关重要。颈动脉机体对低氧的反应并不是一致的，而是表现出显着的个体间差异。颈动脉体氧感觉变化的分子机制尚不清楚。低氧诱导因子-1(HIF-1)和低氧诱导因子-2(HIF-2)介导对低氧的转录反应。本文综述了新的证据表明，HIF-α亚型的正确表达是颈动脉小体O2传感的关键分子决定因素。缺氧诱导因子-1α缺乏导致颈动脉体钝的缺氧反应，这是由于缺氧诱导因子-2α的丰度增加，抗氧化酶活性升高，细胞内氧化还原状态降低所致。相反，缺氧诱导因子-2α缺乏会导致颈动脉小体对低氧的敏感性增强，这是由于缺氧诱导因子-1α的丰度增加、促氧化物酶活性升高以及细胞内氧化还原状态所致。HIF-1α和HIF-2α同样降低的双重杂合子小鼠在氧化还原状态或颈动脉体氧感觉方面没有异常。因此，HIF-α亚型之间的相互拮抗决定了氧化还原状态，从而建立了颈动脉小体感知低氧的设定点。
Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Carotid body responses to hypoxia are not uniform but instead exhibit remarkable inter-individual variations. The molecular mechanisms underlying variations in carotid body O2 sensing are not known. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate transcriptional responses to hypoxia. This article reviews the emerging evidence that proper expression of the HIF-α isoforms is a key molecular determinant for carotid body O2 sensing. HIF-1α deficiency leads to a blunted carotid body hypoxic response, which is due to increased abundance of HIF-2α, elevated anti-oxidant enzyme activity, and a reduced intracellular redox state. Conversely, HIF-2α deficiency results in augmented carotid body sensitivity to hypoxia, which is due to increased abundance of HIF-1α, elevated pro-oxidant enzyme activity, and an oxidized intracellular redox state. Double heterozygous mice with equally reduced HIF-1α and HIF-2α showed no abnormality in redox state or carotid body O2 sensing. Thus, mutual antagonism between HIF-α isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body.