慢性间歇低氧对颏舌肌线粒体自噬的影响以及脂联素的干预机制

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an oxidative stress disease characterized by chronic intermittent hypoxia(CIH), which is induced by partial or complete obstruction of upper airway during sleep. It presents the pathogenesis similar to ischemia/reperfusion injury. Impaired mitochondria caused by hypoxia is eliminated by way of mitophagy, so as to avoid cell apoptosis. Disturbances of mitophagy induced by CIH in cardiomyocytes resulted in cell apoptosis. Dysfunction of genioglossus is an important pathogenesis of OSAHS. However, there has been no report about the effect of CIH on genioglossal mitophagy. Adiponectin(Ad) is a cytokine secreted by adipose tissue. Recent researches suggested that myocardial contractibility could be improved by Ad via increasing autophagy. Our studies have revealed that dysfunction of genioglossal contractibility caused by CIH could be improved by supplement of exogenous adiponectin. Our pre-experiment has found CIH led to decrease of mitophagy, which could be improved by supplement of exogenous Ad. Therefore, we speculate that decrease of mitophagy in genioglossal cells may be an important mechanism of CIH-induced impairment and dysfunction of genioglossus. This project was designed to explore the effect of CIH on mitophagy in genioglossus and the protective mechanism of Ad by animal and cell experiments. We consider this study will be helpful to clarify the pathogenesis of impairment and dysfunction of genioglossus during OSAHS and provide new thoughts for specific novel treatments of OSAHS.

阻塞性睡眠呼吸暂停综合征（OSAHS）是一种睡眠时因上气道部分或完全闭塞导致慢性间歇低氧（CIH）的氧化应激性疾病，机制类似缺氧-再灌注损伤。低氧造成线粒体损害可通过线粒体自噬清除，避免细胞凋亡发生。CIH可诱发心肌细胞线粒体自噬功能障碍，导致细胞凋亡。颏舌肌功能障碍是OSAHS重要发病机制，但CIH是否影响颏舌肌细胞线粒体自噬尚无报道。脂联素（Ad）是脂肪分泌的一种细胞因子，有报道显示其可能通过改善自噬提高心肌收缩功能。我们前期研究已证实补充外源性Ad可以改善颏舌肌收缩功能。预实验发现CIH可导致颏舌肌线粒体自噬下调，补充外源性Ad可改善之。科学假设：CIH诱发线粒体自噬水平下调是颏舌肌收缩功能障碍的重要机制。本课题拟通过动物和细胞实验探讨CIH对颏舌肌线粒体自噬的影响以及Ad的保护机制，为进一步阐明OSAHS中颏舌肌收缩功能障碍的机制提供理论基础，也为寻找新的治疗方法提供思路。

本研究通过成功建立模拟阻塞性睡眠呼吸暂停（OSA）病理损害特点的间歇性低氧（CIH）大鼠模型，观察和探讨了CIH对大鼠颏舌肌线粒体自噬功能的影响以及补充外源性脂联素的作用。研究显示，CIH可引起颏舌肌线粒体自噬功能的改变，从而影响线粒体超微结构和线粒体的功能，最终影响颏舌肌收缩功能；而补充外源性脂联素则可明显缓解和防止上述病理变化，结果还显示脂联素发挥此作用可能通过AMPK信号传导通路。本研究预期目的达到，结果对于阐明OSA的发病机制和临床采用脂联素作为防止CIH 对颏舌肌的损伤具有重要的指导意义。围绕本课题，目前已发表SCI论文1篇，参加国际学术会议发表交流2次；基于此研究基础，课题负责人成功入选世界睡眠协会（World Sleep Society）组织的2019年首届国际睡眠研究培训项目（International Sleep Research Training Program，ISRTP），荣幸成为甄选出的5名学员之一，于斯坦福大学睡眠医学中心访学一年。