Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Clinical Centre for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, China.
J Cell Physiol. 2019 May;234(5):6324-6335. doi: 10.1002/jcp.27363. Epub 2018 Sep 24.
Pulmonary hypertension (PH) is prevalent in patients with obstructive sleep apnea (OSA) syndrome, and coexistence of PH and OSA indicates a worse prognosis and higher mortality. Chronic intermittent hypoxia (CIH) is the key pathogenesis of OSA. Also, microRNA-223 (miR-223) plays a role in the regulation of CIH-induced PH process. However, the detailed mechanism of CIH inducing PH is still unclear. This study aimed to investigate the pathological process of CIH associated PH and explore the potential therapeutic methods. In this study, adult Sprague-Dawley rats were exposed to CIH or normoxic (N) conditions with 2-methoxyestradiol (2-Me) or vehicle treatment for 6 weeks. The results showed that 2-Me treatment reduced the progression of pulmonary angiogenesis in CIH rats, and alleviated proliferation, cellular migration, and reactive oxygen species formation was induced by CIH in pulmonary artery smooth muscle cells (PASMCs). CIH decreased the expression of miR-223, whereas 2-Me reversed the downregulation of miR-223 both in vivo and in vitro. Furthermore, the antiangiogenic effect of 2-Me observed in PASMCs was abrogated by miR-223 inhibitor, while enhanced by miR-223 mimic. These findings suggested that miR-223 played an important role in the process of CIH inducing PH, and 2-Me might reverse CIH-induced PH via upregulating miR-223.
肺动脉高压（PH）在阻塞性睡眠呼吸暂停（OSA）综合征患者中较为常见，PH 和 OSA 的共存表明预后更差，死亡率更高。慢性间歇性低氧（CIH）是 OSA 的关键发病机制。此外，microRNA-223（miR-223）在调节 CIH 诱导的 PH 过程中发挥作用。然而，CIH 诱导 PH 的详细机制尚不清楚。本研究旨在探讨 CIH 相关 PH 的病理过程，并探索潜在的治疗方法。在这项研究中，成年 Sprague-Dawley 大鼠暴露于 CIH 或常氧（N）条件下，并用 2-甲氧基雌二醇（2-Me）或载体处理 6 周。结果表明，2-Me 治疗可减轻 CIH 大鼠肺血管生成的进展，并减轻 CIH 诱导的肺动脉平滑肌细胞（PASMC）增殖、细胞迁移和活性氧形成。CIH 降低了 miR-223 的表达，而 2-Me 则在体内和体外均逆转了 miR-223 的下调。此外，在 PASMC 中观察到的 2-Me 的抗血管生成作用被 miR-223 抑制剂阻断，而被 miR-223 模拟物增强。这些发现表明，miR-223 在 CIH 诱导 PH 的过程中发挥重要作用，而 2-Me 可能通过上调 miR-223 来逆转 CIH 诱导的 PH。
