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，其患病风险增加两倍 心血管疾病，并增加各种原因造成的死亡率。短暂停止时的间歇性低氧(IH) 阻塞性睡眠呼吸暂停导致内皮细胞炎症，这是阻塞性睡眠呼吸暂停综合征发生和发展的关键步骤 心血管疾病。然而，介导IH诱导的内皮炎症的机制仍然存在 OSA的血管表现尚不清楚，因此没有针对性的治疗方法。vbl.使用 我们从OSA患者新鲜获取的内皮细胞(ECs)中发现补体抑制功能受损 作为IH患者内皮炎症的初始刺激，从而首次将补体激活联系在一起 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因子CD59，一种质膜蛋白， 抑制终末补体膜攻击复合体(MAC)的形成并保护宿主细胞 在OSA患者中，从EC表面内化的补体损伤。随后的MAC沉积 启动IH的内皮炎症，核因子-kappa B和核转位是证据 炎性细胞因子表达增加。重要的是，我们表明IH并不显著地影响 无补体时内皮细胞核因子-kappaB活性和促炎细胞因子水平 提示补体激活在阻塞性睡眠呼吸暂停综合征的内皮炎症中起重要作用。有趣的是， CD59在IH中的内化似乎是胆固醇依赖的，他汀类药物阻止内皮细胞上MAC沉积 在IH中CD59依赖的方式，提示了一种新的治疗策略来降低OSA的血管风险。 这让我们假设，IH诱导的细胞胆固醇积聚通过以下途径减少补体抑制 内皮细胞表面CD59内化增加导致MAC沉积增加 阻塞性睡眠呼吸暂停综合征的炎症和功能障碍及CPAP和/或他汀类药物治疗可逆转内皮细胞 通过恢复对补体的抑制而导致功能障碍。为了实现这一目标，我们提出了以下3个具体建议 目的：1)确定补体抑制减少是否促进阻塞性睡眠呼吸暂停低通气综合征患者的内皮功能障碍。 CPAP是否逆转这些变化，2)以确定是否介导了减少的补体抑制 通过阻塞性睡眠呼吸暂停患者内皮细胞中胆固醇的积累以及CPAP是否逆转这些变化，以及3)确定 他汀类药物是否通过使用随机对照保留补体抑制来预防阻塞性睡眠呼吸暂停综合征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细胞，拟议的研究可能 加深对阻塞性睡眠呼吸暂停综合征血管功能障碍的认识，为新的临床试验提供依据 治疗策略，如在标准的CPAP治疗中增加他汀类药物，以预防和/或 逆转阻塞性睡眠呼吸暂停综合征的血管风险。

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.