Heterozygous HIF-1α deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia
Heterozygous HIF-1α deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia
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DOI：
10.1113/jphysiol.2006.114033
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发表时间：
2006-12-01
影响因子：
5.5
通讯作者：
Prabhakar, Nanduri R.
中科院分区：
文献类型：
--
作者：
Peng, Ying-Jie;Yuan, Guoxiang;Prabhakar, Nanduri R.
慢性间歇性低氧(CIH)发生于睡眠呼吸暂停患者，对多种生理功能有不良影响。以往的研究表明，颈动脉小体产生的反射介导了CIH诱发的心肺反应，而活性氧(ROS)在诱发对CIH的全身反应中起着重要作用。目前对脑出血的分子机制知之甚少。转录激活因子低氧诱导因子-1(HIF-1)介导了广泛的细胞和系统对低氧的反应，HIF-1在暴露于IH的细胞培养中被激活。在目前的研究中，我们研究了CIH是否激活了HIF-1，如果是的话，它是否有助于小鼠的心肺反应和ROS的产生。实验在部分缺乏HIF-1α(O-2调节的HIF-1复合体亚单位)的野生型(WT)和杂合型(HET)雄性小鼠上进行。两组小鼠均暴露于脑出血10天(15 S低氧后常氧5分钟，9次发作h(-1)，8 h d(-1))或21%O2(对照组)10天。颈动脉机体对低氧的反应增强，急性间歇性低氧(AIH)诱导了感觉长期促进(SLTF)的化学感受器活性。与此形成鲜明对比的是，在CIH暴露的HET小鼠中，低氧感觉反应未受影响，AIH不能有效地诱导sLTF。对暴露于CIH的WT小鼠的心肺反应的分析显示，低氧呼吸反应增强，呼吸的LTF，血压升高和血浆去甲肾上腺素增加。与之形成鲜明对比的是，在暴露于CIH的HET小鼠中，这些反应要么缺失，要么减弱。在CIH暴露的WT小鼠中，ROS升高，而HET小鼠则没有这种反应。四(1-甲基-4-吡啶)卟啉五氯锰是一种有效的超氧化物清除剂，它不仅能阻止CIH诱导的WT小鼠体内ROS的升高，而且还能抑制CIH诱导的HIF-1α的上调。这些结果表明：(A)HIF-1的激活在诱导CIH诱导的颈动脉体介导心肺反应中起关键作用；(B)CIH增加ROS；(C)CIH的作用涉及HIF-1和ROS之间复杂的正相互作用。
Chronic intermittent hypoxia (CIH) occurs in patients with sleep apnoea and has adverse effects on multiple physiological functions. Previous studies have shown that reflexes arising from carotid bodies mediate CIH-evoked cardio-respiratory responses, and reactive oxygen species (ROS) play important roles in eliciting systemic responses to CIH. Very little is known about the molecular mechanisms underlying CIH. The transcriptional activator hypoxia-inducible factor-1 (HIF-1) mediates a broad range of cellular and systemic responses to hypoxia, and HIF-1 is activated in cell cultures exposed to IH. In the present study we examined whether CIH activates HIF-1 and if so whether it contributes to cardio-respiratory responses and ROS generation in mice. Experiments were performed on male littermate wild-type (WT) and heterozygous (HET) mice partially deficient in HIF-1 alpha, the O-2 regulated subunit of the HIF-1 complex. Both groups of mice were exposed to either 10 days of CIH (15 s of hypoxia followed by 5 min of normoxia, 9 episodes h(-1), 8 h day(-1)) or to 10 days of 21% O-2 (controls). Carotid body response to hypoxia was augmented, and acute intermittent hypoxia (AIH) induced sensory long-term facilitation (sLTF) of the chemoreceptor activity in CIH-exposed WT mice. In striking contrast, hypoxic sensory response was unaffected and AIH was ineffective in eliciting sLTF in CIH-exposed HET mice. Analysis of cardio-respiratory responses in CIH-exposed WT mice revealed augmented hypoxic ventilatory response, LTF of breathing, elevated blood pressures and increased plasma noradrenaline. In striking contrast these responses were either absent or attenuated in HET mice exposed to CIH. In CIH-exposed WT mice, ROS were elevated and this response was absent in HET mice. Manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride, a potent scavenger of superoxide, not only prevented CIH-induced increases in ROS but also CIH-evoked HIF-1 alpha up-regulation in WT mice. These results indicate that: (a) HIF-1 activation is critical for eliciting CIH-induced carotid body-mediated cardio-respiratory responses; (b) CIH increases ROS; and (c) the effects of CIH involve complex positive interactions between HIF-1 and ROS.