Vascular Endothelial Activation in Sleep Apnea

睡眠呼吸暂停中的血管内皮激活

• 批准号: 8268434
• 负责人: Sanja Jelic
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268434
• 关键词: 3-nitrotyrosine; Address; Adherence; Adult; Affect; American; Atherosclerosis; Blood Vessels; Breathing; Cardiovascular Diseases; Cardiovascular Manifestation; Cardiovascular system; Collection; Continuous Positive Airway Pressure; Coronary Arteriosclerosis; Data; Development; Early identification; Endothelial Cells; Endothelium; Forearm; Frequencies; Harvest; Health Care Costs; Human; Hypertension; Hypoxia; Inflammation; Ischemic Stroke; Lead; Ligands; Link; Mediating; Morphologic artifacts; NF-kappa B; Nature; Obstructive Sleep Apnea; Pathway interactions; Patients; Peptides; Peripheral; Population; Preventive; Relative (related person); Risk; Sampling; Signal Pathway; Sleep Apnea Syndromes; Techniques; Testing; Therapeutic; Vascular Diseases; Vascular Endothelium; Veins; Venous; base; cardiovascular disorder risk; cardiovascular risk factor; effective therapy; human NOS3 protein; inflammatory marker; minimally invasive; mortality; novel diagnostics; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; prolyl-serine; tryptophyl-proline

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.

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。阻塞性睡眠呼吸暂停综合症的有效治疗降低了阻塞性睡眠呼吸暂停综合症患者心血管疾病的风险。然而，阻塞性睡眠呼吸暂停综合征仍然经常没有被认识到，大多数阻塞性睡眠呼吸暂停综合征患者没有坚持标准的持续气道正压治疗。OSA的认知率低，对标准治疗的依从性差，凸显了对OSA心血管表现的新的诊断和治疗方法的迫切需要。阻塞性睡眠呼吸暂停时反复出现的缺氧/复氧导致动脉和静脉外周内皮细胞的激活，这是心血管疾病发生和发展的关键步骤。我们开发了一种从前臂浅静脉采集内皮细胞的微创技术，可以安全地采集和直接检查内皮细胞，而不需要阻塞性睡眠呼吸暂停患者的培养条件。利用新鲜获取的内皮细胞，我们直接证明了阻塞性睡眠呼吸暂停综合征患者外周内皮细胞的激活，其证据是核因子kappa B和硝基酪氨酸的表达增加，内皮型一氧化氮合酶的表达减少。反复缺氧/复氧是睡眠呼吸暂停综合征特有的现象，它可能通过特定的途径激活外周血管内皮细胞。阻塞性睡眠呼吸暂停综合征患者血管内皮细胞激活的全身性提示存在以血管内皮细胞为靶点并与其接触的循环内源性配体。我们已经确定FHENWPS(Phe-His-Glu-Asn-Trp-Pro-Ser)是OSA患者在临床明显的心血管疾病发生之前靶向和激活内皮细胞的特异性配体。这导致我们假设配体FHENWPS与OSA的外周血管内皮细胞激活有关，从而可能加速心血管疾病的发生和发展。为了解决这一假设，我们建议：(1)确定配体FHENWPS在无明显心血管疾病的OSA患者CPAP治疗前后的存在(目标1)，(2)确定配体FHENWPS对OSA患者外周内皮细胞激活和全身炎症的影响(目标2)，以及(3)确定配体FHENWPS是否增强OSA合并冠心病患者的外周内皮细胞激活和全身炎症(目标3)。利用一种新的方法来表征人的血管内皮细胞，这些研究可能会促进我们对OSA中血管内皮细胞激活的理解，并可能允许(1)早期识别OSA患者存在血管疾病的风险，(2)为功能研究提供基础，从而可能导致开发新的治疗策略来预防和/或逆转OSA的血管风险。