缺氧诱导因子与阻塞性睡眠呼吸暂停。
Hypoxia-inducible factors and obstructive sleep apnea.
出版信息
J Clin Invest. 2020 Oct 1;130(10):5042-5051. doi: 10.1172/JCI137560.
Abstract
Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.
摘要
间歇性低氧（IH）是阻塞性睡眠呼吸暂停（OSA）的一个显著特征，OSA 是一种广泛存在的呼吸紊乱。本综述重点关注缺氧诱导因子（HIFs）在 OSA 中所见的 O2 模式的 IH 实验模型中高血压、2 型糖尿病（T2D）和认知能力下降中的作用。IH 增加 HIF-1α 并降低 HIF-2α 蛋白水平。失调的 HIFs 通过 HIF-1 依赖性激活促氧化剂酶基因增加活性氧（ROS），此外，HIF-2 还会降低抗氧化基因的转录。ROS 反过来激活化学感受器反射并抑制压力感受器反射，从而刺激交感神经系统并导致高血压。我们还讨论了 HIF-1 引起的 ROS 生成如何导致 IH 诱导的胰岛素抵抗和 T2D 以及海马中 NMDA 受体信号的破坏，从而导致认知能力下降。
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3
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