Purinergic signaling in sleep apnea

描述(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%的成年人口。除了白天嗜睡，OSA还与心血管疾病的发病有关，包括全身和肺高压、冠状动脉疾病、充血性心力衰竭、中风、心律失常和心脏性猝死。阻塞性睡眠呼吸暂停综合征影响心血管系统的机制可能与胸腔内压升高、交感神经兴奋增加以及随后的间歇性低氧(IH)有关。缺氧缺血性脑损伤通过氧化应激、炎症和内皮型一氧化氮合酶(ENOS)活性的降低而导致内皮功能障碍，eNOS是一种负责产生一氧化氮的酶，其生物利用度是内皮细胞正常功能的关键。尽管阻塞性睡眠呼吸暂停综合征是一种研究得相当充分的疾病，但阻塞性睡眠呼吸暂停综合征对血管系统的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嘌呤能受体作用，减少高糖诱导的ROS形成，减轻肿瘤坏死因子α的炎症效应，并挽救在高糖浓度下培养的人内皮细胞的eNOS活性。我们新的体内数据表明，在糖尿病、动脉粥样硬化倾向于载脂蛋白E缺陷小鼠的主动脉弓中，给予三磷酸腺苷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在血管中分子靶点的相似性，我们推测，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。这项资助提案旨在阐明P2受体信号转导的有益作用的分子基础，并作为睡眠呼吸暂停的模型，为细胞外核苷酸预防间歇性低氧相关血管病变的有效性提供体内证据。我们认为，细胞外核苷酸通过维持足够的eNOS功能，减少ROS的产生，并通过减弱促炎信号来保护血管内皮细胞免受IH的损害。迫切需要寻找治疗阻塞性睡眠呼吸暂停综合征相关并发症的新靶点。我们认为，P2受体是保护血管系统免受氧化应激和炎症的一个有前途的靶点，就像在OSA中观察到的那样。 公共卫生意义：阻塞性睡眠呼吸暂停是一种呼吸障碍，至少影响4%的成年人口。大量数据表明，睡眠呼吸暂停与心血管发病率和死亡率有关，此外，睡眠呼吸暂停与肥胖和代谢综合征的标志物有关。我们提出了一种新的方法来保护血管免受阻塞性睡眠呼吸暂停的有害影响。

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.