Vascular Endothelial Activation in Sleep Apnea

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是一种影响四分之一美国成年人的疾病，与心血管疾病风险增加和全因死亡率增加密切相关。有效治疗OSA可降低OSA患者发生心血管疾病的风险。然而，阻塞性睡眠呼吸暂停仍然经常被忽视，大多数阻塞性睡眠呼吸暂停患者不坚持标准的持续气道正压通气治疗。OSA的低识别率和标准治疗的依从性差强调了对OSA心血管表现的新诊断和治疗方法的迫切需要。在OSA中短暂停止呼吸期间反复发作的缺氧/复氧导致动脉和静脉外周内皮激活，这是心血管疾病发展和进展的关键步骤。我们已经开发了一种从前臂浅静脉获取内皮细胞的微创技术，该技术允许在OSA患者中安全收集和直接检查内皮细胞，而不会产生培养条件的伪影。使用新鲜收获的内皮细胞，我们已经证明了OSA患者的直接外周内皮活化，这可以通过核因子κ B和硝基酪氨酸形成的表达增加以及内皮型一氧化氮合酶的表达减少来证明。反复缺氧/复氧是睡眠呼吸暂停特有的现象，可通过特定途径激活外周内皮细胞。OSA中内皮激活的系统性性质表明存在靶向和接合内皮细胞的循环内源性配体。我们已经鉴定了肽FHENWPS（Phe-His-Glu-Asn-Trp-Pro-Ser）作为在临床上明显的心血管疾病发作之前靶向并激活OSA患者中的内皮细胞的特异性配体。这使我们假设配体FHENWPS与OSA中的外周内皮活化相关，从而可能加速心血管疾病的发展和进展。为了解决这一假设，我们建议：（1）确定配体FHENWPS在CPAP治疗前后在没有明显心血管疾病的OSA患者中的存在（目的1），（2）确定配体FHENWPS对OSA中外周内皮活化和全身炎症的作用（目的2），以及（3）确定配体FHENWPS是否增强OSA和并存CAD患者的外周内皮活化和全身炎症（目的3）。使用一种新的方法来表征人类血管内皮，拟议的研究可能会促进我们对OSA中内皮激活的理解，并可能允许（1）早期识别具有血管疾病风险的OSA患者，以及（2）为功能研究提供基础，这些研究可能导致开发预防和/或逆转OSA中血管风险的新治疗策略。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA), a condition that affects a quarter of American adults, is strongly and independently associated with an increased risk for cardiovascular diseases and increased all-cause mortality. Effective treatment of OSA reduces the risk of cardiovascular diseases in patients with OSA. However, OSA remains frequently unrecognized and a majority of OSA patients do not adhere to standard continuous positive airway pressure therapy. Low rate of OSA recognition and poor adherence with standard therapy underscores the urgent need for novel diagnostic and therapeutic approaches to cardiovascular manifestations of OSA. Repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing in OSA lead to activation of both arterial and venous peripheral endothelium, a key step in the development and progression of cardiovascular diseases. We have developed a minimally invasive technique of endothelial harvesting from a superficial forearm vein that allows safe collection and direct examination of endothelial cells without the artifact of culture conditions in OSA patients. Using freshly harvested endothelial cells, we have demonstrated directly peripheral endothelial activation in OSA patients as evidenced by increased expression of nuclear factor kappa B and nitrotyrosine formation and reduced expression of endothelial nitric oxide synthase. Repetitive hypoxia/reoxygenation, a phenomenon unique to sleep apnea, may activate the peripheral endothelium through specific pathways. The systemic nature of endothelial activation in OSA suggests the presence of circulating endogenous ligands that target and engage endothelial cells. We have identified peptide FHENWPS (Phe-His-Glu-Asn-Trp-Pro-Ser) as a specific ligand that targets and activates endothelial cells in OSA patients prior to onset of clinically evident cardiovascular diseases. This led us to hypothesize that ligand FHENWPS is associated with peripheral endothelial activation in OSA and thereby may accelerate the development and progression of cardiovascular diseases. To address this hypothesis, we are proposing: (1) To determine the presence of ligand FHENWPS in OSA patients without overt cardiovascular diseases before and after CPAP therapy (Aim 1), (2) To determine the effects of ligand FHENWPS on peripheral endothelial activation and systemic inflammation in OSA (Aim 2), and (3) To determine whether ligand FHENWPS augments peripheral endothelial activation and systemic inflammation in patients with OSA and coexistent CAD (Aim 3). Using a novel approach to characterize human vascular endothelium, the proposed studies may advance our understanding of endothelial activation in OSA and may allow (1) early identification of OSA patients who are at risk for vascular diseases and (2) provide basis for functional studies that may lead to the development of novel therapeutic strategies for preventing and/or reversing vascular risk in OSA.