Purinergic signaling in sleep apnea

睡眠呼吸暂停中的嘌呤能信号传导

• 批准号: 8031548
• 负责人: ELZBIETA KACZMAREK
• 金额: $ 24.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8031548
• 关键词: Adult; Affect; Animal Model; Aorta; Apolipoprotein E; Applications Grants; Arrhythmia; Atherosclerosis; Attenuated; Biological Availability; Blood Vessels; Breathing; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell Culture Techniques; Cell physiology; Cells; Clinical; Complications of Diabetes Mellitus; Congestive Heart Failure; Coronary Arteriosclerosis; Data; Diabetes Mellitus; Disease; Effectiveness; Endothelial Cells; Endothelium; Enzymes; Fluorescent Probes; Functional disorder; Generations; Glucose; Heat shock proteins; Human; Hyperglycemia; Hypoxia; Impairment; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Link; Measures; Mediator of activation protein; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; NADP; NF-kappa B; Nitric Oxide; Nucleotides; Obesity; Obstructive Sleep Apnea; Outcome Measure; Oxidases; Oxidative Stress; Pathogenesis; Patients; Phosphorylation; Population; Proteins; Pulmonary Hypertension; Purinergic P2 Receptors; Reactive Oxygen Species; Receptor Signaling; Regulation; Role; Scheme; Signal Transduction; Sleep Apnea Syndromes; Source; Stroke; Syndrome; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular System; Work; Xanthine Oxidase; analog; aortic arch; attenuation; base; biological adaptation to stress; diabetic; extracellular; functional disability; human CYBA protein; human NOS3 protein; improved; in vivo; insight; mortality; new therapeutic target; nitration; novel strategies; pressure; prevent; protective effect; protein activation; receptor; stress protein; sudden cardiac death

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is a breathing disorder that affects at least 4% of the adult population. Beside daytime sleepiness, OSA has been implicated in the pathogenesis of cardiovascular diseases, including systemic and pulmonary hypertension, coronary artery disease, congestive heart failure, stroke, cardiac arrhythmias, and sudden cardiac death. The mechanisms by which OSA affects the cardiovascular system may result from excursions in intrathoracic pressure, increased sympathetic activation, and subsequent intermittent hypoxia (IH). IH induces endothelial dysfunction via oxidative stress by increased generation of reactive oxygen species (ROS), inflammation, and impairment of the activity of endothelial nitric oxide synthase (eNOS), an enzyme responsible for generation of nitric oxide, whose bioavailability is key for proper function of the endothelium. Even though OSA is a fairly well investigated disease, the mechanistic insights into OSA effects on the vasculature remain to be elucidated. We have recent evidence that extracellular nucleotides, such as ATP, ADP and UTP, acting via specific P2 purinergic receptors, decrease high glucose- induced ROS formation, attenuate inflammatory effects of tumor necrosis factor alpha, and rescue eNOS activity in human endothelial cells cultured in high glucose concentrations. Our new in vivo data indicate that ATP administration decreases the expression of oxidative stress-related and proinflammatory proteins in aortic arches of diabetic, atherosclerosis-prone ApoE-deficient mice. Given the similarity in molecular targets of high glucose and IH in the vasculature, we hypothesize that the protective effects of purinergic signaling observed in endothelial cells exposed to high glucose could also be pertinent to patients with OSA. This grant proposal is aimed at elucidating the molecular basis of the beneficial effects of P2 receptor signaling, and providing an in vivo proof of principle for extracellular nucleotide effectiveness in preventing vasculopathy associated with intermittent hypoxia, as a model of sleep apnea. We propose that extracellular nucleotides protect the endothelium from the damaging effects of IH by maintaining adequate eNOS function, decreasing ROS generation, and by attenuating proinflammatory signaling. Finding of new therapeutic targets for OSA-related complications are urgently required. We suggest that P2 receptors are a promising target for the protection of vasculature from oxidative stress and inflammation, such as those observed in OSA. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea is a breathing disorder that affects at least 4% of the adult population. Numerous data point to the association of sleep apnea and cardiovascular morbidity and mortality, and in addition link sleep apnea with obesity and with markers of the metabolic syndrome. We propose a novel approach to protect vasculature from deleterious effects of obstructive sleep apnea.

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是一种呼吸障碍，影响至少4%的成年人。除了白天嗜睡，OSA还与心血管疾病的发病机制有关，包括全身性和肺动脉高压、冠状动脉疾病、充血性心力衰竭、中风、心律失常和心源性猝死。OSA影响心血管系统的机制可能是由胸内压升高、交感神经激活增加和随后的间歇性缺氧（IH）引起的。IH通过氧化应激诱导内皮功能障碍，增加活性氧（ROS）的生成、炎症和内皮一氧化氮合酶（eNOS）活性的损害，eNOS是一种负责生成一氧化氮的酶，其生物利用度是内皮正常功能的关键。尽管阻塞性睡眠呼吸暂停是一种研究相当充分的疾病，但阻塞性睡眠呼吸暂停对脉管系统影响的机制仍有待阐明。我们最近有证据表明，细胞外核苷酸，如ATP， ADP和UTP，通过特定的P2嘌呤能受体起作用，减少高糖诱导的ROS形成，减轻肿瘤坏死因子α的炎症作用，并在高葡萄糖浓度培养的人内皮细胞中恢复eNOS活性。我们新的体内实验数据表明，在糖尿病、易发生动脉粥样硬化的apoe缺陷小鼠的主动脉弓中，ATP管理降低了氧化应激相关蛋白和促炎蛋白的表达。鉴于高糖和IH在血管中的分子靶点相似，我们假设在高糖暴露的内皮细胞中观察到的嘌呤能信号的保护作用也可能与OSA患者有关。该资助提案旨在阐明P2受体信号传导有益作用的分子基础，并为细胞外核苷酸在预防间歇性缺氧相关血管病变（作为睡眠呼吸暂停的模型）方面的有效性提供体内原理证明。我们提出细胞外核苷酸通过维持足够的eNOS功能、减少ROS生成和减弱促炎信号来保护内皮免受IH的破坏作用。迫切需要寻找新的治疗靶点来治疗osa相关并发症。我们认为P2受体是保护血管免受氧化应激和炎症的一个有希望的靶点，例如在OSA中观察到的那些。