Oxidant Signaling in Pulmonary Hypertension

肺动脉高压中的氧化信号

• 批准号: 10720584
• 负责人: THOMAS C RESTA
• 金额: $ 58.62万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720584
• 关键词: Acute; Agonist; Airway Disease; Altitude; Animal Model; Blood; Cell Proliferation; Cell membrane; Cell model; Cholesterol; Cholesterol Homeostasis; Chronic; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Clinical; Couples; Coupling; Data; Disease; Distal; Edema; Electron Transport; Epidermal Growth Factor Receptor; Functional disorder; G-Protein-Coupled Receptors; Generations; Heart; Hypoxia; Impairment; Knowledge; Laboratories; Link; Lung; Lung diseases; Maintenance; Mechanics; Mediating; Membrane; Microfilaments; Mission; Mitochondria; Morbidity - disease rate; Mus; NADPH Oxidase; National Heart, Lung, and Blood Institute; Oxidants; Pathway interactions; Patients; Peripheral; Pilot Projects; Population; Preparation; Preventive measure; Process; Production; Progressive Disease; Proliferating; Pulmonary Circulation; Pulmonary Emphysema; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary arterial remodeling; Rare Diseases; Reactive Oxygen Species; Regulation; Research; Rodent Model; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Sleep Apnea Syndromes; Sleep Disorders; Smooth Muscle Myocytes; Source; Stimulus; Stretching; Testing; Tissue Model; Vascular Diseases; Vascular resistance; Vasoconstrictor Agents; World Health Organization; arterial remodeling; caveolin 1; cholesterol trafficking; constriction; effective therapy; genetic approach; human model; hypoxia-induced pulmonary hypertension; innovation; lung hypoxia; mitochondrial dysfunction; mitochondrial membrane; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pharmacologic; pulmonary arterial hypertension; pulmonary vascular disorder; pulmonary vasoconstriction; response; right ventricular failure; src-Family Kinases; uptake; vasoconstriction

PROJECT SUMMARY Pulmonary vascular dysfunction resulting from chronic hypoxia (CH) leads to increased vascular resistance and resultant pulmonary hypertension (PH) in patients with chronic obstructive pulmonary diseases, sleep ap- nea, restrictive lung diseases, and in residents at high altitude. The resulting increase in afterload on the right heart often leads to clinical manifestations of cor pulmonale, peripheral edema, morbidity and mortality. Alt- hough it is widely considered that pulmonary arterial constriction and remodeling are central to this disease process, the mechanisms linking CH to these responses are poorly understood. The overall objective of the current study is to identify oxidant signaling mechanisms responsible for spon- taneous pulmonary arterial smooth muscle cell (PASMC) tone and enhanced vasoconstrictor reactivity in CH- induced PH. Based on preliminary data, our central hypothesis is that PASMC Cav1 dysfunction following CH disrupts cellular cholesterol homeostasis that confers transduction of mechanical, electrical and GPCR stimuli to mitochondrial Ca2+ uniporter (MCU)-dependent mitochondrial reactive oxygen species (mtROS) generation, vasoconstriction, and pHTN. We plan to test this hypothesis by pursuing the following specific aims: Specific Aim #1: Establish the mechanism by which CH reduces PASMC membrane cholesterol leading to enhanced vasoconstrictor reactivity and cell proliferation. Hypothesis: CH couples vasoconstrictor stimuli to PASMC myofilament Ca2+ sensitization and proliferation through impaired Cav1-mediated cholesterol trafficking to the cell membrane. Specific Aim #2: Define the signaling mechanism by which CH increases PASMC mtROS generation, vaso- constriction, and cell proliferation. Hypothesis: Cav1 dysfunction following CH causes mitochondrial membrane cholesterol accumulation and MCU-dependent mtROS generation required for augmented PASMC contractility and proliferation. Specific Aim #3: Determine the contribution of Cav1, MCU and mtROS to CH-induced pHTN. Hypothesis: Cav1 dysregulation and MCU-induced mtROS production contribute to the progression and maintenance of CH-induced pHTN. We anticipate this project will define an innovative paradigm of PASMC signaling involving regulation of mtROS generation and Ca2+ sensitization by Cav1-mediated disruption of cellular cholesterol homeostasis that is unique to the pulmonary circulation. The proposed studies are significant because they are expected to ver- tically impact our understanding of regulation of oxidant signaling mechanisms by Cav1 and membrane cho- lesterol, and their contribution to CH-induced pHTN. In doing so, they have potential to provide new thera- peutic strategies to treat pHTN that target components of this signaling pathway.

项目概要 慢性缺氧（CH）引起的肺血管功能障碍导致血管阻力增加 慢性阻塞性肺疾病患者的肺动脉高压（PH）、睡眠障碍 nea、限制性肺部疾病以及高海拔地区的居民。由此产生的右侧后负荷增加 心脏疾病常导致肺心病、外周水肿等临床表现，发病率和死亡率高。替代- 尽管人们普遍认为肺动脉收缩和重塑是这种疾病的核心 然而，对于将 CH 与这些反应联系起来的机制知之甚少。 当前研究的总体目标是确定负责自发性的氧化信号传导机制。 CH-肺动脉平滑肌细胞 (PASMC) 张力和血管收缩反应性增强 诱导PH值。根据初步数据，我们的中心假设是 CH 后 PASMC Cav1 功能障碍 破坏细胞胆固醇稳态，从而实现机械、电和 GPCR 刺激的转导 线粒体 Ca2+ 单向转运蛋白 (MCU) 依赖的线粒体活性氧 (mtROS) 生成， 血管收缩和pHTN。我们计划通过追求以下具体目标来检验这一假设： 具体目标#1：建立 CH 降低 PASMC 膜胆固醇的机制，从而导致 增强血管收缩反应性和细胞增殖。 假设：CH 将血管收缩刺激与 PASMC 肌丝 Ca2+ 致敏和增殖结合起来 通过受损的 Cav1 介导的胆固醇向细胞膜的运输。 具体目标 #2：定义 CH 增加 PASMC mtROS 生成、血管- 收缩和细胞增殖。 假设：CH 后 Cav1 功能障碍导致线粒体膜胆固醇积累， 增强 PASMC 收缩性和增殖所需的 MCU 依赖性 mtROS 生成。 具体目标#3：确定 Cav1、MCU 和 mtROS 对 CH 诱导的 pHTN 的贡献。 假设：Cav1 失调和 MCU 诱导的 mtROS 产生有助于进展和 维持CH诱导的pHTN。 我们预计该项目将定义 PASMC 信号传导的创新范例，涉及调节 Cav1 介导的细胞胆固醇稳态破坏导致 mtROS 产生和 Ca2+ 敏化 是肺循环所特有的。拟议的研究意义重大，因为它们预计将验证 显着影响我们对 Cav1 和膜胆碱受体调节氧化信号机制的理解 甾醇及其对 CH 诱导的 pHTN 的贡献。通过这样做，他们有潜力提供新的治疗方法 针对该信号通路成分的治疗 pHTN 的治疗策略。