Vascular Endothelial Activation in Sleep Apnea

摘要 阻塞性睡眠呼吸暂停 (OSA) 是一种影响四分之一西方成年人的疾病，使罹患此病的风险增加三倍 心血管疾病并增加全因死亡率。短暂停止期间间歇性缺氧 (IH) OSA 中呼吸的减少会导致内皮炎症，这是 OSA 发生和进展的关键步骤 心血管疾病。然而，介导 IH 诱导的内皮炎症的机制仍然存在 尚不清楚，因此，没有针对 OSA 血管表现的靶向治疗。使用 从 OSA 患者新鲜采集的内皮细胞 (EC) 中，我们发现补体抑制受损 作为 IH 中内皮炎症的初始刺激，从而首次连接补体激活 OSA 的血管风险。我们发现一种主要的补体抑制剂 CD59，一种质膜蛋白， 抑制末端补体膜攻击复合物 (MAC) 的形成并保护宿主细胞 来自 OSA 患者的补体损伤，从 EC 表面内化。随后的 MAC 沉积 在 IH 中引发内皮炎症，核因子 kappa B 的核易位证明了这一点 炎症细胞因子表达增加。重要的是，我们表明 IH 不会显着影响 在补体缺失的情况下，EC 中的核因子-κ B 活性和促炎细胞因子水平， 表明补体激活在 OSA 的内皮炎症中起着重要作用。有趣的是， IH 中 CD59 的内化似乎是胆固醇依赖性的，他汀类药物可防止 MAC 在 EC 上沉积 以 CD59 依赖性方式在 IH 中发挥作用，提出了一种降低 OSA 血管风险的新治疗策略。 这使我们推测 IH 诱导的细胞胆固醇积累通过以下方式减少补体抑制： EC 表面 CD59 的内化增加，导致 MAC 沉积增加，内皮细胞 OSA 的炎症和功能障碍以及用 CPAP 和/或他汀类药物治疗 OSA 可逆转内皮细胞 通过恢复补体抑制功能障碍。为实现这一目标，我们提出以下3项具体要求： 目的：1) 确定补体抑制减少是否会促进 OSA 和 OSA 患者的内皮功能障碍 CPAP 是否可以逆转这些变化，2) 确定补体抑制减少是否是介导的 通过 OSA 中 EC 中的胆固醇积累以及 CPAP 是否可以逆转这些变化，以及 3) 确定 他汀类药物是否通过随机保留补体抑制来预防 OSA 中的内皮功能障碍 设计。使用创新方法来表征人类血管内皮，拟议的研究可能 增进我们对 OSA 血管功能障碍的理解，并为新型药物的临床试验提供基础 治疗策略，例如在标准 CPAP 治疗中添加他汀类药物，以预防和/或 逆转 OSA 的血管风险。

Abstract Obstructive sleep apnea (OSA), a condition that affects a quarter of the Western adults, triples the risk for cardiovascular diseases and increases all-cause mortality. Intermittent hypoxia (IH) during transient cessation of breathing in OSA leads to endothelial inflammation, a key step in the initiation and progression of cardiovascular disease. However, the mechanisms that mediate IH-induced endothelial inflammation remain unclear and, consequently, no targeted therapy is available for vascular manifestations of OSA. Using endothelial cells (ECs) freshly harvested from OSA patients, we have identified impaired complement inhibition as an initial stimulus for endothelial inflammation in IH, thereby linking for the first time complement activation to vascular risk in OSA. We found that a major complement inhibitor CD59, a plasma membrane protein that inhibits the formation of the terminal complement membrane attack complex (MAC) and protects host cells from complement injury, is internalized from the EC surface in OSA patients. Consequent MAC deposition initiates endothelial inflammation in IH, as evidenced by nuclear translocation of nuclear factor-kappa B and increased expression of inflammatory cytokines. Importantly, we showed that IH does not significantly affect nuclear factor-kappa B activity and levels of pro-inflammatory cytokines in ECs in the absence of complement, suggesting that complement activation has an essential role in endothelial inflammation in OSA. Interestingly, internalization of CD59 in IH appears to be cholesterol-dependent and statins prevent MAC deposition on ECs in IH in a CD59-dependent manner, suggesting a novel therapeutic strategy to reduce vascular risk in OSA. This led us to hypothesize that IH-induced cellular cholesterol accumulation reduces complement inhibition via increased internalization of CD59 from the EC surface leading to increased MAC deposition, endothelial inflammation and dysfunction in OSA and that treatment of OSA with CPAP and/or statins reverses endothelial dysfunction by restoring complement inhibition. To accomplish this goal we propose the following 3 Specific Aims: 1) To determine whether reduced complement inhibition promotes endothelial dysfunction in OSA and whether CPAP reverses these changes, 2) To determine whether reduced complement inhibition is mediated by cholesterol accumulation in ECs in OSA and whether CPAP reverses these changes, and 3) To determine whether statins prevent endothelial dysfunction in OSA by preserving complement inhibition using randomized design. Using an innovative approach to characterize human vascular endothelium, the proposed studies may advance our understanding of vascular dysfunction in OSA and provide the basis for clinical trials of novel therapeutic strategies, such as addition of statins to the standard CPAP therapy, for preventing and/or reversing vascular risk in OSA.