Vascular Endothelial Activation in Sleep Apnea

摘要 阻塞性睡眠呼吸暂停（OSA），一种影响四分之一西方成年人的疾病， 心血管疾病和增加全因死亡率。短暂停药期间的间歇性缺氧（IH） 阻塞性睡眠呼吸暂停导致内皮炎症，这是阻塞性睡眠呼吸暂停的开始和进展的关键步骤。 心血管疾病然而，介导IH诱导的内皮炎症的机制仍然存在， 不清楚，因此，没有靶向治疗可用于OSA的血管表现。使用 内皮细胞（EC）新鲜收获的OSA患者，我们已经确定受损的补体抑制 作为IH中内皮炎症的初始刺激，从而首次将补体激活 阻塞性睡眠呼吸暂停综合征的血管风险我们发现一种主要的补体抑制剂CD 59，一种质膜蛋白， 抑制末端补体膜攻击复合物（MAC）的形成并保护宿主细胞 从补体损伤，是内在的EC表面在OSA患者。CONSTRUCTION MAC沉积 在IH中启动内皮炎症，如核因子-κ B的核转位所证明， 炎性细胞因子的表达增加。重要的是，我们发现IH不会显著影响 核因子-κ B活性和不存在补体时EC中促炎细胞因子的水平， 提示补体激活在OSA的内皮炎症中具有重要作用。有趣的是， IH中CD 59的内化似乎是胆固醇依赖性的，他汀类药物可防止MAC沉积在EC上 在IH中以CD 59依赖性方式表达，提示了一种新的治疗策略，以降低OSA的血管风险。 这使我们假设IH诱导的细胞胆固醇积累通过以下途径降低补体抑制： EC表面的CD 59内化增加，导致MAC沉积增加，内皮 OSA中炎症和功能障碍以及用CPAP和/或他汀类药物治疗OSA逆转了内皮 通过恢复补体抑制功能障碍。为了实现这一目标，我们提出以下三个具体建议： 目的：1）确定减少的补体抑制是否促进OSA中的内皮功能障碍， CPAP是否逆转这些变化，2）为了确定是否介导了补体抑制减少 通过OSA中EC中的胆固醇积累以及CPAP是否逆转这些变化，以及3）确定 他汀类药物是否通过保留补体抑制作用预防OSA患者的内皮功能障碍 设计使用一种创新的方法来表征人类血管内皮，拟议的研究可能 提高我们对OSA血管功能障碍的认识，并为新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，用于预防和/或 扭转阻塞性睡眠呼吸暂停的血管风险。

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.