Obstructive sleep apnea syndrome promotes the progression of aortic dissection via a ROS-HIF-1α-MMPs associated pathway
Obstructive sleep apnea syndrome promotes the progression of aortic dissection via a ROS-HIF-1α-MMPs associated pathway
复制标题
阻塞性睡眠呼吸暂停综合征通过 ROS-HIF-1α-MMPs 相关途径促进主动脉夹层的进展
DOI：
10.7150/ijbs.34888
复制
发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Zeng, Hesong
中科院分区：
文献类型：
--
作者：
Liu, Wanjun;Zhang, Wenjun;Zeng, Hesong
目的：阻塞性睡眠呼吸暂停综合征（OSA）越来越被认为是主动脉夹层（AD）的独立危险因素，并且与间歇性缺氧和重新氧合（IH）的程度密切相关。这项研究旨在阐明ROS-HIF-1 Alpha-MMP途径在AD发病机理中的作用，以及HIF-1α抑制剂是否减弱AD形成。方法和结果：8周大的雄性APOE（ - / - ）小鼠在β-氨基二氮蛋白酶的浓度上以3周或2周的浓度为OSMOTORINE，以OSMOTION的浓度为0.1％。 Ng/min/kg血管紧张素II（ANG II）2周。为了模仿OSA，一组暴露于IH，其中由20.9％O2/8％O2 FiO2（每小时30次）的交替循环组成，在12小时的光相中，在Nadir Fio2的20 s，在ANG II输注前2周，在Nadir Fio2中。输注后，我们通过超声心动图，组织学和免疫组织化学分析评估了主动脉中的重塑。与仅ANG II组相比，IH治疗导致腔面积显着扩大，介质的破坏，明显的增厚，较高的AD形成发生率和较低的存活率。此外，IH暴露显着增加了主动脉ROS的产生和随后的HIF-1α表达，进而促进了VEGF，MMP2和MMP9的表达，并最终导致AD的发展。此外，体外研究证实，IH诱导的HIF-1α表达在MMP的诱导中起着重要作用，并且受PI3K/AKT/FRAP途径的调节。有趣的是，选择性的HIF-1α抑制剂KC7F2可以显着改善IH暴露在体外和体内诱发的有害效应。结论：OSAS诱导的IH可以通过ROSHIF-1 Alpha-MMPS相关的途径促进AD的发生和进展。选择性HIF-1α抑制剂KC7F2可能是AD患者的新型治疗剂。
Aims: Obstructive sleep apnea syndrome (OSAS) has been increasingly recognized as an independent risk factor for aortic dissection (AD) and it is strongly associated with the extent of intermittent hypoxia and re-oxygenation (IH). This study aimed to clarify role of ROS- HIF-1α-MMPs pathway in the pathogenesis of AD and whether the HIF-1α inhibitor attenuates AD formation. Methods and results: 8-week-old male ApoE-/- mice were given β-aminopropionitrile at a concentration of 0.1 % for 3 weeks and infused via osmotic mini pumps with either saline or 2,500 ng/min/kg angiotensin II (Ang II) for 2 weeks. To mimic the OSAS, one group was exposed to IH, which consisted of alternating cycles of 20.9% O2/8% O2 FiO2 (30 episodes per hour) with 20 s at the nadir FiO2 during the 12-h light phase, 2 weeks before Ang II infusion. After Ang II infusion, we assessed remodeling in the aorta by echocardiography, histological and immunohistochemical analysis. IH treatment resulted in significant enlargement of the luminal area, destruction of the media, marked thickening of the adventitia, higher incidence of AD formation and lower survival rate in compared with the Ang II only group. Moreover, IH exposure markedly increased the aortic ROS production and subsequent HIF-1α expression, which in turn promoted the expressions of VEGF, MMP2 and MMP9 and finally leading to the progression of AD. Besides, in vitro study confirmed that IH induced HIF-1α expression plays an important role in the induction of MMPs and that is regulated by the PI3K/AKT/FRAP pathway. Intriguingly, a selective HIF-1α inhibitor KC7F2 could significantly ameliorate IH exposure induced aforementioned deleterious effects in vitro and in vivo. Conclusion: OSAS induced IH can promote the occurrence and progression of AD via a ROS- HIF-1α-MMPs associated pathway. The selective HIF-1α inhibitor KC7F2 could be a novel therapeutic agent for AD patient with OSAS.