NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia.
NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia.
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DOI：
10.1523/jneurosci.4768-08.2009
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Prabhakar NR
中科院分区：
文献类型：
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作者：
Peng YJ;Nanduri J;Yuan G;Wang N;Deneris E;Pendyala S;Natarajan V;Kumar GK;Prabhakar NR
呼吸运动神经元对缺氧的反应本质上是反射性的，颈动脉体感觉感受器构成了这种反射的传入支。最近的研究表明，反复低氧暴露可引起慢性间歇性低氧（CIH）啮齿动物颈动脉体感觉神经放电（sLTF）的长时程易化。虽然抗氧化剂的研究表明活性氧（ROS）介导的信号转导参与引发sLTF，但与ROS产生相关的来源和机制尚未研究。我们检验了NADPH氧化酶（NOX）产生的ROS介导CIH诱发的sLTF的假设。对暴露于CIH或常氧10天的大鼠和小鼠的离体颈动脉体进行实验。急性重复缺氧诱发CIH中NOX活性增加~12倍，但在对照颈动脉体中没有，这种效应与NOX 2 mRNA和蛋白的上调有关，其主要定位于颈动脉体的球细胞。sLTF被NOX抑制剂阻止，并且在NOX 2缺陷的小鼠中不存在。通过CIH激活NOX需要5-HT释放和5-HT 2受体的激活与PKC信号传导偶联。ROS清除剂的研究表明，O2·−产生的H2 O2有助于sLTF。用H2 O2引发从常氧对照大鼠和小鼠的颈动脉体的sLTF，类似于在CIH处理的动物中观察到的。这些观察结果揭示了一个新的作用，氮氧化物诱导的活性氧信号在介导的感觉可塑性的颈动脉体。
Respiratory moto-neuron response to hypoxia is reflex in nature and carotid body sensory receptor constitutes the afferent limb of this reflex. Recent studies showed that repetitive exposures to hypoxia evokes long term facilitation of sensory nerve discharge (sLTF) of the carotid body in rodents exposed to chronic intermittent hypoxia (CIH). Although studies with anti-oxidants suggested the involvement of reactive oxygen species (ROS)-mediated signaling in eliciting sLTF, the source of and the mechanisms associated with ROS generation have not yet been investigated. We tested the hypothesis that ROS generated by NADPH oxidase (NOX) mediate CIH-evoked sLTF. Experiments were performed on ex vivo carotid bodies from rats and mice exposed either to 10 days of CIH or normoxia. Acute repetitive hypoxia evoked a ~12 fold increase in NOX activity in CIH but not in control carotid bodies, and this effect was associated with up-regulation of NOX2 mRNA and protein, which was primarily localized to glomus cells of the carotid body. sLTF was prevented by NOX inhibitors and was absent in mice deficient in NOX2. NOX activation by CIH required 5-HT release and activation of 5-HT2 receptors coupled to PKC signaling. Studies with ROS scavengers revealed that H2O2 generated from O2·− contributes to sLTF. Priming with H2O2 elicited sLTF of carotid bodies from normoxic control rats and mice, similar to that seen in CIH treated animals. These observations reveal a novel role for NOX-induced ROS signaling in mediating sensory plasticity of the carotid body.