lncRNA-MALAT1作为ceRNA参与miR-218调控慢性间歇低氧诱导内皮细胞凋亡的作用机制

Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a sleep disorder that causes multiple system organ damage. Chronic intermittent hypoxemia (CIH) is a pathophysiological basis of its associated complications. In our previous study, miR-218 was found to be upregulated in CIH endothelial cells, and knockdown of miR-218 expression significantly reduced the expression of HIF-1α (HIF-1α) and the induction of CIH by inhibiting the activation of Robo1 Aortic endothelial cell apoptosis. Based on our previous study and combined the latest advances in international research, we involve the ceRNA mechanism into CIH-induced endothelial injury which is regulated by miR-218. Combined with the bioinformatics which predicted the interactions between miR-218 and lncRNA, we intend to explore the relationship between lncRNA which has the function of ceRNA and miR-218, and to find the role of lncRNA in CIH-induced endothelial injury and its mechanism. Meanwhile, the effects of methylation of lncRNA encoding gene on the expression of lncRNA-MALAT1 and endothelial cell apoptosis will also be analyzed.These will provide theoretical and experimental basis for verifying the mechanism of OSAHS-related cardiovascular injury and identifying biomarker for the early diagnosis and prognosis in OSAHS-related cardiovascular injury.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是一种导致多系统多器官损伤的睡眠障碍性疾病，慢性间歇低氧(CIH)是其相关并发症的病理生理基础。我们前期研究发现，miR-218在CIH内皮细胞中表达上调，阻遏miR-218表达可通过抑制Robo1的激活而显著降低缺氧诱导因子-1α（HIF-1α）的表达，减轻CIH下的主动脉内皮细胞凋亡。本项目在此基础上结合最新的国际研究前沿进展，将ceRNA机制引入miR-218调控CIH内皮细胞损伤中，结合生物信息学预测及与miR-218存在互作关系的lncRNA，探讨发挥ceRNA功能的lncRNA与miR-218之间的调控关系及lncRNA调控CIH内皮损伤的作用及机制，同时分析编码lncRNA基因甲基化对lncRNA-MALAT1表达及内皮细胞凋亡的影响，为OSAHS相关心血管损伤的发生发展机制、诊断分子标志物的筛选以及临床治疗提供理论基础和实验依据。

阻塞性睡眠呼吸暂停低通气综合征(Obstructive sleep apnea hypopnea syndrome, OSAHS)可引起多系统多脏器损害，尤其是心血管系统，是高血压、冠心病等的独立危险因素。因此，探索OSAHS相关心血管损伤的机制及寻找有用的标志物对防治心血管并发症具有较大的意义。课题组从血管内皮细胞及心肌细胞出发，建立动物间歇低氧模型，应用载体构建和基因转染技术、慢病毒包装、荧光素酶报告基因实验、生物信息学分析等方法，发现：①Lnc MALAT1通过充当miR-142-3p的海绵增强了HMGB1的表达，引起内皮细胞损伤。②miR-193a-3p抑制可以通过负向调节FAIM2来保护内皮细胞免受IH诱导的损伤。③miR-146a-5p可以通过靶向XIAP降低H9c2的活力，促进H9c2细胞凋亡，从而加重IH诱导的心肌细胞损伤。④miR-3574可以通过靶向Axin1缓解IH诱导的心肌细胞损伤。⑤LncRNA XR_596701可通过miR-344b-5p/FAIM3轴对IH诱导的心肌细胞的增殖和凋亡起到保护作用。⑥PPARγ可能通过影响线粒体功能导致内皮细胞凋亡损伤。本项目揭示了lncRNA-MALAT1、miR-193a-3p、miR-146a-5p、miR-3574及IncRNA XR_596701在间歇低氧下内皮细胞及心肌细胞损伤中相关机制，为防治或减轻慢性间歇低氧造成的心血管损伤提供新的思路和途径。