Vascular Smooth Muscle Signaling in Intermittent Hypoxia-Induced Pulmonary Hypertension

间歇性缺氧引起的肺动脉高压中的血管平滑肌信号传导

• 批准号: 9330238
• 负责人: THOMAS C RESTA
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330238
• 关键词: Actins; Agonist; Altitude; Animal Model; Animals; Arteries; Cardiovascular Diseases; Cells; Chronic; Chronic Obstructive Airway Disease; Comorbidity; Data; Development; Diastolic heart failure; Disease; Edema; Electron Transport; Etiology; F-Actin; G Actin; Generations; Heart; Human; Hypoxia; Image; Incidence; Inner mitochondrial membrane; Knowledge; Laboratories; Lead; Ligands; Lung; Lung diseases; Maintenance; Mediating; Mediator of activation protein; Metabolic Diseases; Microfilaments; Mission; Mitochondria; Modeling; Morbidity - disease rate; Mus; Muscle Contraction; Muscle Tonus; NADPH Oxidase; National Heart, Lung, and Blood Institute; Nonmuscle Myosin Type IIA; Outcome; Oxidative Stress; Pathway interactions; Patients; Peripheral; Pharmacology; Pickwickian Syndrome; Population; Preparation; Prevalence; Preventive measure; Production; Protocols documentation; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Reactive Oxygen Species; Research; Risk Factors; Rodent; Rodent Model; Role; Sarcolemma; Scaffolding Protein; Signal Pathway; Signal Transduction; Sleep Apnea Syndromes; Sleep Disorders; Source; Syndrome; Testing; Vascular Diseases; Vascular Smooth Muscle; Vascular resistance; Vasoconstrictor Agents; Video Microscopy; World Health Organization; arterial remodeling; base; clinically relevant; effective therapy; genetic approach; individualized medicine; innovation; mortality; new therapeutic target; novel; polymerization; pressure; protein kinase C beta; receptor; residence; response; treatment strategy; vasoconstriction

PROJECT SUMMARY Pulmonary vascular dysfunction resulting from chronic intermittent hypoxia (CIH) leads to pulmonary hypertension (pHTN) in patients with sleep apnea. Despite the growing recognition, prevalence, and impact of this disorder, the mechanisms involved in this response are poorly understood. The overall objective of the current study is to identify vascular smooth muscle (VSM) signaling mechanisms responsible for PKCβ-mediated pulmonary vasoconstriction, and the role of this signaling pathway in CIH-dependent increases in vasoconstrictor reactivity, arterial remodeling and pHTN. Based on preliminary data, our guiding hypothesis is that PKCβ mediates pulmonary vasoconstriction through a novel mechanism involving interaction with the scaffolding protein PICK1, activation of mitochondrial KATP (mitoKATP) channels, mitochondrial ROS (mitoROS) generation, and actin polymerization. Furthermore, we hypothesize that this signaling axis mediates enhanced vasoconstrictor reactivity, arterial remodeling and pHTN following CIH. We plan to test these hypotheses by pursuing the following specific aims: 1. Determine the role of PKCβ–mitoROS signaling in enhanced arterial constrictor reactivity and pulmonary hypertension following CIH. Hypothesis: The PKCβ/mitoROS signaling axis contributes to the progression and maintenance of CIH- induced pHTN through contractile and mitogenic actions in VSM. 2. Define the signaling mechanism by which PKCβ stimulates mitoROS generation in pulmonary VSM and increased vasoconstrictor sensitivity after CIH. Hypothesis: CIH enhances agonist-dependent pulmonary vasoconstriction via PICK1-dependent activation of mitoKATP channels and subsequent mitoROS production 3. Establish the contribution of actin polymerization to PKCβ-induced VSM contraction and the role of this mechanism in augmented pulmonary arterial vasoconstrictor reactivity following CIH. Hypothesis: CIH augments agonist-induced pulmonary VSM Ca2+ sensitization and vasoconstriction through PKCβ and mitoROS-dependent actin polymerization. We anticipate that this project will define an innovative paradigm of VSM signaling involving PKCβ, mitoROS generation, actin polymerization and Ca2+ sensitization that is unique to the pulmonary circulation, and the role of this pathway in the development of pHTN in a clinically relevant rodent model of sleep apnea. These studies are significant because they are expected to vertically impact our understanding of vasoconstrictor mechanisms that contribute to CIH-induced pHTN, and therefore have potential to yield unique treatment strategies for sleep apnea-associated pHTN and other cardiovascular and metabolic disorders in which PKCβ signaling is a central player.

项目摘要 慢性间歇性缺氧（CIH）引起的肺血管功能障碍导致肺动脉高压， 高血压（pHTN）睡眠呼吸暂停患者。尽管越来越多的认识，流行，和影响， 对于这种疾病，这种反应的机制还知之甚少。 目前研究的总体目标是确定血管平滑肌（VSM）信号 PKCβ介导的肺血管收缩的机制，以及这种信号传导的作用 在CIH依赖性增加血管收缩反应性，动脉重塑和pHTN的途径。基于 初步数据显示，我们的指导假设是PKCβ通过一种新的途径介导肺血管收缩 涉及与支架蛋白PICK 1相互作用的机制，线粒体KATP（mitoKATP）的激活 通道、线粒体ROS（mitoROS）生成和肌动蛋白聚合。此外，我们假设 这一信号轴介导增强的血管收缩反应性、动脉重塑和pHTN， CIH我们计划通过追求以下具体目标来检验这些假设： 1.确定PKCβ-mitoROS信号在增强的动脉收缩反应性中的作用， CIH后肺动脉高压 假设：PKCβ/mitoROS信号轴参与CIH的进展和维持。 诱导pHTN通过收缩和促有丝分裂作用在VSM。 2.明确PKCβ刺激肺VSM中线粒体ROS生成的信号机制 CIH后血管收缩敏感性增加。 假设：CIH通过PICK 1依赖性激活增强激动剂依赖性肺血管收缩 mitoKATP通道和随后的mitoROS产生 3.确定肌动蛋白聚合在PKCβ诱导的VSM收缩中的作用以及 CIH后肺动脉血管收缩反应增强的机制。 假设：CIH增强激动剂诱导的肺VSM Ca 2+增敏和血管收缩 通过PKCβ和线粒体依赖性肌动蛋白聚合。 我们预计，这个项目将定义一个创新的范式VSM信号转导涉及PKCβ， 线粒体ROS生成、肌动蛋白聚合和肺循环特有的Ca 2+敏化， 以及该途径在临床相关的睡眠呼吸暂停啮齿动物模型中pHTN发展中的作用。 这些研究意义重大，因为它们有望垂直影响我们对 血管收缩机制，有助于CIH诱导的pHTN，因此有潜力产生独特的 睡眠呼吸暂停相关pHTN和其他心血管和代谢疾病的治疗策略 其中PKCβ信号是一个重要角色。