Institute for Integrative Physiology and Center for Systems Biology of Oxygen Sensing, Biological Sciences Division, University of Chicago, Chicago, IL, USA.
Adv Exp Med Biol. 2018;1071:109-114. doi: 10.1007/978-3-319-91137-3_14.
Sleep apnea with periodic cessation of breathing during sleep is a highly prevalent respiratory disorder affecting an estimated 10% of adults. Patients with sleep apnea exhibit several co-morbidities including hypertension, stroke, disrupted sleep, and neurocognitive and metabolic complications. Emerging evidence suggests that a hyperactive carotid body (CB) chemo reflex is an important driver of apneas in sleep apnea patients. Gasotransmitters carbon monoxide (CO) and hydrogen sulfide (HS) play important roles in oxygen sensing by the CB. We tested the hypothesis that an augmented CB chemo reflex stemming from disrupted CO-HS signaling may lead to sleep apnea. This possibility was tested in mice deficient in hemeoxygenase-2 (HO-2), an enzyme involved in CO synthesis, which were shown to exhibit hyperactive CB activity due to high HS levels. We found that HO-2 mice exhibit a high incidence of apneas during sleep compared to wild type mice. Blocking the CB hyperactivity with L-propargylglycine, an inhibitor of cystathionine-γ-lyase (CSE), which catalyzes HS synthesis, prevented apneas in HO-2 mice. These findings suggest that targeting CB with inhibitors of CSE might be a novel therapeutic strategy for preventing sleep apnea.
睡眠呼吸暂停是一种常见的呼吸系统疾病，估计有 10%的成年人受其影响。睡眠呼吸暂停患者表现出多种合并症，包括高血压、中风、睡眠中断以及神经认知和代谢并发症。新出现的证据表明，颈动脉体（CB）化学反射亢进是睡眠呼吸暂停患者呼吸暂停的重要驱动因素。气体递质一氧化碳（CO）和硫化氢（HS）在 CB 的氧感应中发挥重要作用。我们假设，源自 CO-HS 信号中断的 CB 化学反射亢进可能导致睡眠呼吸暂停。这一可能性在缺乏血红素加氧酶-2（HO-2）的小鼠中得到了检验，HO-2 是一种参与 CO 合成的酶，由于 HS 水平升高，其 CB 活性表现出亢进。我们发现，与野生型小鼠相比，HO-2 小鼠在睡眠期间出现呼吸暂停的发生率较高。用 L-丙炔基甘氨酸（一种催化 HS 合成的胱硫醚-γ-裂解酶（CSE）的抑制剂）阻断 CB 活性亢进可防止 HO-2 小鼠出现呼吸暂停。这些发现表明，用 CSE 的抑制剂靶向 CB 可能是预防睡眠呼吸暂停的一种新的治疗策略。
