Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, University of Chicago, Chicago, Illinois.
J Neurophysiol. 2021 Jun 1;125(6):2054-2067. doi: 10.1152/jn.00067.2021. Epub 2021 Apr 28.
Chronic intermittent hypoxia (CIH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread breathing disorder. CIH-treated rodents exhibit activation of the sympathetic nervous system and hypertension. Heightened carotid body (CB) activity has been implicated in CIH-induced hypertension. CB expresses high abundance of olfactory receptor (Olfr) 78, a G-protein coupled receptor. Olfr 78 null mice exhibit impaired CB sensory nerve response to acute hypoxia. Present study examined whether Olfr78 participates in CB-dependent activation of the sympathetic nervous system and hypertension in CIH-treated mice and in hemeoxygenase (HO)-2 null mice experiencing CIH as a consequence of naturally occurring OSA. CIH-treated wild-type (WT) mice showed hypertension, biomarkers of sympathetic nerve activation, and enhanced CB sensory nerve response to hypoxia and sensory long-term facilitation (sLTF), and these responses were absent in CIH-treated Olfr78 null mice. HO-2 null mice showed higher apnea index (AI) (58 ± 1.2 apneas/h) than WT mice (AI = 8 ± 0.8 apneas/h) and exhibited elevated blood pressure (BP), elevated plasma norepinephrine (NE) levels, and heightened CB sensory nerve response to hypoxia and sLTF. The magnitude of hypertension correlated with AI in HO-2 null mice. In contrast, HO-2/Olfr78 double null mice showed absence of elevated BP and plasma NE levels and augmented CB response to hypoxia and sLTF. These results demonstrate that Olfr78 participates in sympathetic nerve activation and hypertension and heightened CB activity in two murine models of CIH. Carotid body (CB) sensory nerve activation is essential for sympathetic nerve excitation and hypertension in rodents treated with chronic intermittent hypoxia (CIH) simulating blood O profiles during obstructive sleep apnea (OSA). Here, we report that CIH-treated mice and hemeoxygenase (HO)-2-deficient mice, which show OSA phenotype, exhibit sympathetic excitation, hypertension, and CB activation. These effects are absent in Olfr78 null and Olfr78/HO-2 double null mice.
慢性间歇性低氧（CIH）是阻塞性睡眠呼吸暂停（OSA）的标志表现，是一种广泛存在的呼吸障碍。CIH 处理的啮齿动物表现出交感神经系统的激活和高血压。颈动脉体（CB）活性的增强与 CIH 诱导的高血压有关。CB 表达大量嗅觉受体（Olfr）78，一种 G 蛋白偶联受体。Olfr78 缺失小鼠表现出对急性低氧的 CB 感觉神经反应受损。本研究检查了 Olfr78 是否参与 CIH 处理的小鼠中的 CB 依赖性交感神经激活和高血压，以及由于自然发生的 OSA 而经历 CIH 的血红素加氧酶（HO）-2 缺失小鼠。CIH 处理的野生型（WT）小鼠表现出高血压、交感神经激活的生物标志物，以及对低氧和感觉长期易化（sLTF）的 CB 感觉神经反应增强，而这些反应在 CIH 处理的 Olfr78 缺失小鼠中不存在。HO-2 缺失小鼠的呼吸暂停指数（AI）（58 ± 1.2 次呼吸暂停/小时）高于 WT 小鼠（AI = 8 ± 0.8 次呼吸暂停/小时），并表现出血压升高、血浆去甲肾上腺素（NE）水平升高，以及对低氧和 sLTF 的 CB 感觉神经反应增强。HO-2 缺失小鼠的高血压程度与 AI 相关。相比之下，HO-2/Olfr78 双缺失小鼠表现出缺乏升高的血压和血浆 NE 水平以及增强的 CB 对低氧和 sLTF 的反应。这些结果表明，Olfr78 参与了两种 CIH 啮齿动物模型中的交感神经激活和高血压以及 CB 活性的升高。颈动脉体（CB）感觉神经的激活对于模拟阻塞性睡眠呼吸暂停（OSA）期间血液 O 谱的慢性间歇性低氧（CIH）处理的啮齿动物的交感神经兴奋和高血压是必不可少的。在这里，我们报告 CIH 处理的小鼠和血红素加氧酶（HO）-2 缺失的小鼠，其表现出 OSA 表型，表现出交感神经兴奋、高血压和 CB 激活。这些效应在 Olfr78 缺失和 Olfr78/HO-2 双缺失小鼠中不存在。
