Vascular Endothelial Activation in Sleep Apnea

睡眠呼吸暂停中的血管内皮激活

• 批准号: 8114718
• 负责人: Sanja Jelic
• 金额: $ 40.02万
• 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/8114718
• 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. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea (OSA) affects 25% of American adults. OSA is strongly and independently associated with an increased risk for cardiovascular diseases and increased all-cause mortality. Incomplete understanding of the mechanisms that triple the risk for cardiovascular diseases in OSA precludes the development of effective preventive and therapeutic strategies for cardiovascular complications of OSA. Repetitive hypoxia during transient cessation of breathing in OSA alters function of the vascular endothelium, a key step in the development and progression of atherosclerosis and cardiovascular diseases. Using a novel approach to characterize vascular endothelium, we propose to identify specific molecules and their endothelial cell targets that promote endothelial alterations in patients with OSA. Unraveling of the signaling pathways of endothelial alterations in OSA may allow (1) early identification of OSA patients who are at risk for cardiovascular diseases, and (2) the development of novel therapeutic approaches for preventing and/or reversing cardiovascular 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且独立。 OSA 的有效治疗可降低 OSA 患者患心血管疾病的风险。然而，OSA 经常未被识别，并且大多数 OSA 患者不遵守标准的持续气道正压通气治疗。 OSA 识别率低和标准治疗依从性差，凸显了对 OSA 心血管表现的新诊断和治疗方法的迫切需要。 OSA 患者呼吸短暂停止期间反复发生的缺氧/复氧会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进展的关键步骤。我们开发了一种从前臂浅静脉采集内皮细胞的微创技术，可以安全采集并直接检查 OSA 患者的内皮细胞，而不会影响培养条件。使用新鲜收获的内皮细胞，我们证明了 OSA 患者的外周内皮直接激活，核因子 kappa B 表达增加和硝基酪氨酸形成以及内皮一氧化氮合酶表达减少证明了这一点。重复缺氧/复氧是睡眠呼吸暂停所特有的现象，可能通过特定途径激活外周内皮。 OSA 中内皮激活的全身性质表明存在靶向并参与内皮细胞的循环内源性配体。我们已经确定肽 FHENWPS（Phe-His-Glu-Asn-Trp-Pro-Ser）是一种特异性配体，可在 OSA 患者出现临床明显的心血管疾病之前靶向并激活内皮细胞。这使我们推测配体 FHENWPS 与 OSA 中的外周内皮激活相关，从而可能加速心血管疾病的发生和进展。为了解决这一假设，我们建议：(1) 确定在 CPAP 治疗前后无明显心血管疾病的 OSA 患者中配体 FHENWPS 的存在（目标 1），(2) 确定配体 FHENWPS 对外周内皮激活的影响和 OSA 的全身炎症（目标 2），以及 (3) 确定配体 FHENWPS 是否增强 OSA 和共存 CAD 患者的外周内皮活化和全身炎症（目标 3）。使用一种新方法来表征人类血管内皮，拟议的研究可能会增进我们对 OSA 中内皮激活的理解，并可能允许 (1) 早期识别有血管疾病风险的 OSA 患者，以及 (2) 为以下功能研究提供基础：可能会导致开发预防和/或逆转 OSA 血管风险的新治疗策略。 公共卫生相关性：阻塞性睡眠呼吸暂停 (OSA) 影响 25% 的美国成年人。 OSA 与心血管疾病风险增加和全因死亡率增加密切相关。对导致 OSA 心血管疾病风险增加三倍的机制的不完全了解阻碍了针对 OSA 心血管并发症制定有效的预防和治疗策略。 OSA 患者短暂呼吸停止期间反复缺氧会改变血管内皮功能，这是动脉粥样硬化和心血管疾病发生和进展的关键步骤。我们建议使用一种表征血管内皮的新方法来识别促进 OSA 患者内皮改变的特定分子及其内皮细胞靶标。揭示 OSA 内皮细胞改变的信号通路可能有助于 (1) 早期识别有心血管疾病风险的 OSA 患者，以及 (2) 开发新的治疗方法来预防和/或逆转 OSA 的心血管风险。