Division of Pulmonary, Allergy, and Critical Care Medicine.
Division of Biostatistics, Columbia University College of Physicians and Surgeons, New York, NY.
Sleep. 2021 Apr 9;44(4). doi: 10.1093/sleep/zsaa286.
Obstructive sleep apnea (OSA) is highly prevalent and triples vascular thromboembolic risk. Intermittent hypoxia (IH) during transient cessation of breathing in OSA impairs endothelial protection against complement. Complement activation stimulates the endothelial release of a pro-thrombotic von Willebrand factor (vWF). We investigated whether increased complement activity in OSA promotes the endothelial release of vWF and pro-inflammatory angiopoietin-2. We further investigated whether improving complement protection with statins reverses these changes.
Using endothelial cells (ECs) and blood collected from OSA patients (n = 109) and controls (n = 67), we assessed whether altered cellular localization of complement inhibitor CD59 in OSA modulates exocytosis of Weibel-Palade bodies (WPB), secretory granules that store vWF and angiopoietin-2. These interactions were also assessed in vitro in ECs exposed to normoxia or IH with or without recombinant complement C9 and with or without atorvastatin.
Circulating levels of angiopoietin-2 were greater in OSA than controls and levels of vWF cleavage products correlated with OSA severity. In cultured ECs, IH enhanced complement-stimulated angiopoietin-2 and vWF release by reducing EC surface and increasing intracellular expression of complement inhibitor CD59. Intracellular CD59 co-localized with WPB in OSA. IH increased binding of intracellular CD59 to syntaxin-3, which dissociated syntaxin-3 from voltage-sensitive calcium channel Cav1.2, and activated WPB exocytosis in a calcium-dependent manner. Atorvastatin reversed IH-enhanced endothelial release of vWF and angiopoietin-2.
IH promotes the complement-mediated release of vWF and angiopoietin-2, which may contribute to pro-thrombotic and pro-inflammatory conditions in OSA. Statin reversed these effects, suggesting a potential approach to reduce cardiovascular risk in OSA.
阻塞性睡眠呼吸暂停（OSA）的发病率很高，其血管血栓栓塞风险增加三倍。OSA 患者呼吸暂停期间间歇性缺氧（IH）会损害内皮细胞对补体的保护作用。补体激活会刺激内皮细胞释放促血栓形成的血管性血友病因子（vWF）。我们研究了 OSA 中补体活性的增加是否会促进内皮细胞释放 vWF 和促炎血管生成素-2。我们进一步研究了他汀类药物改善补体保护作用是否能逆转这些变化。
我们使用内皮细胞（EC）和来自 OSA 患者（n=109）和对照组（n=67）的血液，评估 OSA 中补体抑制剂 CD59 的细胞内定位改变是否调节 Weibel-Palade 体（WPB）的胞吐作用，WPB 是储存 vWF 和血管生成素-2 的分泌颗粒。还在体外评估了在正常氧或 IH 下暴露于重组补体 C9 并联合或不联合阿托伐他汀的 EC 中这些相互作用。
OSA 患者的循环血管生成素-2 水平高于对照组，vWF 裂解产物水平与 OSA 严重程度相关。在培养的 EC 中，IH 通过降低 EC 表面和增加补体抑制剂 CD59 的细胞内表达，增强补体刺激的血管生成素-2 和 vWF 释放。IH 增加了细胞内 CD59 与突触融合蛋白-3 的结合，这会使突触融合蛋白-3 与电压敏感钙通道 Cav1.2 分离，并以钙离子依赖的方式激活 WPB 胞吐作用。阿托伐他汀逆转了 IH 增强的内皮细胞 vWF 和血管生成素-2 的释放。
IH 促进了 vWF 和血管生成素-2 的补体介导释放，这可能导致 OSA 中的促血栓形成和促炎状态。他汀类药物逆转了这些影响，提示他汀类药物可能是降低 OSA 中心血管风险的一种潜在方法。
