Vascular Endothelial Activation in Sleep Apnea

睡眠呼吸暂停中的血管内皮激活

• 批准号: 8475648
• 负责人: Sanja Jelic
• 金额: $ 38.08万
• 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/8475648
• 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）是影响四分之一的美国成年人的疾病，与心血管疾病的风险增加和全因死亡率增加密切相关。 OSA的有效治疗可降低OSA患者心血管疾病的风险。但是，OSA仍然经常无法识别，大多数OSA患者不遵守标准的持续阳性气道压力疗法。 OSA识别率低，标准疗法的依从性较差，强调了对OSA心血管表现的新型诊断和治疗方法的迫切需求。在OSA呼吸的短暂停止期间，缺氧/重氧的重复发作会导致动脉和静脉外周内皮激活，这是心血管疾病发展和发展的关键步骤。我们已经开发了一种从浅表前臂静脉的内皮收获的微创技术，该技术可以安全地收集和直接检查内皮细胞，而无需OSA患者培养条件的伪像。使用新鲜收获的内皮细胞，我们已经证明了OSA患者的外周内皮激活，这可以通过核因子Kappa B和硝基酪氨酸形成的表达增加以及降低内皮一氧化氮合成酶的表达而证明。重复性低氧/重氧是睡眠呼吸暂停所特有的现象，可以通过特定的途径激活周围内皮。 OSA中内皮激活的系统性表明，存在靶向和接合内皮细胞的循环内源性配体。我们已经将肽FHENWPS（PHE-HIS-GLU-ASN-TRP-PRO-SER）确定为一种特定的配体，该配体在临床上证明心血管疾病之前针对OSA患者的内皮细胞靶向和激活。这使我们假设配体FHENWP与OSA中的周围内皮激活有关，从而可能加速心血管疾病的发育和进展。为了解决这一假设，我们提出：（1）确定在CPAP治疗前后没有明显心血管疾病的OSA患者中的配体FHENWP（目标1），（2），确定配体FHENWPS的影响，以确定外周内皮激活和OSA中周围炎症的影响（augen）是否是否确定OSA（AIR）（AIM 2）和（AIM 2）和（3） OSA和共存CAD患者的内皮激活和全身炎症（AIM 3）。拟议的研究使用一种新的方法来表征人体血管内皮，可能会提高我们对OSA中内皮激活的理解，并且可能允许（1）早期鉴定有血管疾病风险的OSA患者，（（2）为可能导致预防和/或逆转OSA的新型治疗策略提供功能研究的基础。