Clock gene dysfunction in patients with obstructive sleep apnea syndrome

时钟基因调节哺乳动物的昼夜节律，而时钟基因的功能障碍可能导致各种疾病。为了研究阻塞性睡眠呼吸暂停综合征(OSAS)是否影响时钟基因的功能，我们在体外和体内检测了Perod1(PER1)的mRNA表达。对8例健康人和8例OSAS患者的血浆去甲肾上腺素、血清IL-6、超敏C反应蛋白(hs-CRP)和外周血中PER1mRNA的表达进行了检测。体外培养细胞在IL-6或去甲肾上腺素刺激下检测PER1mRNA的表达。小鼠体内注射去甲肾上腺素后，检测脑组织中PER1mRNA的表达。OSAS患者血清IL-6、hs-CRP和血浆去甲肾上腺素水平升高，但经CPAP治疗后有所改善。经CPAP治疗后，OSAS患者2：00h外周血中PER1mRNA的表达显著降低。IL-6的刺激在体外不能直接诱导PER1的表达。去甲肾上腺素可诱导小鼠大脑皮层PER1基因的表达。我们首先揭示了OSAS导致时钟基因功能障碍，而CPAP有助于改善这种功能。OSAS患者交感神经兴奋和血浆去甲肾上腺素浓度升高可能是PER1基因表达紊乱的因素之一。

Clock genes regulate mammalian circadian rhythms, and dysfunction of clock genes can contribute to various disorders. To investigate whether obstructive sleep apnea syndrome (OSAS) influences clock gene function, we examined Period1 (Per1) mRNA expression in vitro and in vivo. In 8 healthy subjects and 8 OSAS patients, we measured plasma noradrenaline, serum IL-6, and high-sensitivity CRP (hs-CRP), and Per1 mRNA expression in peripheral whole blood. Expression of Per1 mRNA in cultured cells was examined under IL-6 or noradrenaline stimulation in vitro. After noradrenaline was administered to mice in vivo, Per1 mRNA expression in the brain was examined. The concentrations of serum IL-6, hs-CRP and plasma noradrenaline were elevated in OSAS patients, but improved by CPAP therapy. Per1 mRNA expression in the peripheral blood at 2:00 h significantly decreased by CPAP in OSAS patients. The stimulation with IL-6 did not directly induce Per1 mRNA in vitro. The administration of noradrenaline induced Per1 mRNA in cerebral cortex of mice in vivo. We first revealed that OSAS caused clock gene dysfunction, and CPAP helped to improve it. Sympathetic activation and elevation of the plasma noradrenaline concentration in OSAS may be one of the factors involved in disorders of Per1 mRNA expression.