Purinergic signaling in sleep apnea

睡眠呼吸暂停中的嘌呤能信号传导

• 批准号: 8209060
• 负责人: ELZBIETA KACZMAREK
• 金额: $ 21.75万
• 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 2013-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209060
• 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

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.

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。旁边 由于白天嗜睡，OSA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、心脏 心律失常和心脏性猝死OSA影响心血管系统的机制 可能是由于胸内压偏移、交感神经激活增加以及随后的 间歇性缺氧（IH）。IH通过增加生成的氧化应激诱导内皮功能障碍 活性氧（ROS）、炎症和内皮一氧化氮活性受损 一氧化氮合酶（eNOS）是一种负责产生一氧化氮的酶，其生物利用度是适当 内皮的功能。尽管阻塞性睡眠呼吸暂停症是一种研究得相当充分的疾病，但其机制见解 OSA对血管系统的影响仍有待阐明。我们最近有证据表明 核苷酸，如ATP、ADP和UTP，通过特异性P2嘌呤能受体起作用，降低高血糖。 诱导ROS形成，减弱肿瘤坏死因子α的炎症作用，并拯救eNOS 在高葡萄糖浓度下培养的人内皮细胞中的活性。我们新的体内数据表明， ATP降低主动脉氧化应激相关蛋白和促炎蛋白的表达 糖尿病、动脉粥样硬化倾向的ApoE缺陷小鼠的动脉弓。考虑到高分子靶点的相似性， 葡萄糖和IH在血管中，我们假设观察到的嘌呤能信号的保护作用， 在暴露于高糖的内皮细胞中，也可能与OSA患者有关。这份赠款提案是 旨在阐明P2受体信号传导有益作用的分子基础，并提供一种新的研究方法， 细胞外核苷酸有效预防血管病变的体内原理证明 间歇性缺氧，作为睡眠呼吸暂停的模型。我们认为细胞外核苷酸保护了 通过维持足够的eNOS功能，减少ROS， 生成，并通过减弱促炎信号传导。寻找新的治疗靶点， 迫切需要并发症。我们认为，P2受体是一个有前途的目标，为保护 在一些实施方案中，该组合物可用于预防氧化应激和炎症对血管的影响，例如在OSA中观察到的那些。