Peng Ying-Jie, Zhang Xiuli, Gridina Anna, Chupikova Irina, McCormick David L, Thomas Robert J, Scammell Thomas E, Kim Gene, Vasavda Chirag, Nanduri Jayasri, Kumar Ganesh K, Semenza Gregg L, Snyder Solomon H, Prabhakar Nanduri R
Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.
Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1413-1418. doi: 10.1073/pnas.1620717114. Epub 2017 Jan 23.
Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (HS) as the major effector molecule driving apneas. Genetic ablation of the HS-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2 mice. Pharmacologic inhibition of CSE with l-propargyl glycine prevented apneas in both HO-2 mice and SH rats. These observations demonstrate that dysregulated CO and HS signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.
睡眠呼吸暂停是指睡眠期间呼吸的周期性停止，是一个影响美国超过1000万人的主要健康问题，与包括高血压和中风在内的多种后遗症相关。临床研究表明，异常的颈动脉体（CB）活动可能是睡眠呼吸暂停的一个驱动因素。由于气态分子是CB活动的重要决定因素，它们信号传导的异常可能导致睡眠呼吸暂停。在此，我们报告，缺乏血红素加氧酶-2（HO-2）（其可生成气态分子一氧化碳（CO））的小鼠，在快速眼动（REM）睡眠期间表现出以高呼吸暂停和呼吸浅慢指数为特征的睡眠呼吸暂停。在已知表现出CB功能亢进的高血压前期自发性高血压（SH）大鼠中也观察到类似的高呼吸暂停和呼吸浅慢指数。我们确定气态分子硫化氢（HS）是驱动呼吸暂停的主要效应分子。对HS合成酶胱硫醚-γ-裂解酶（CSE）进行基因敲除可使HO-2小鼠的呼吸恢复正常。用L-炔丙基甘氨酸对CSE进行药理学抑制可预防HO-2小鼠和SH大鼠的呼吸暂停现象。这些观察结果表明，CB中CO和HS信号传导失调会导致呼吸暂停，并提示抑制CSE可能是预防CB驱动的睡眠呼吸暂停的一种有效治疗干预措施。
