Pulmonary Hypertension following Intermittent Hypoxia

间歇性缺氧后肺动脉高压

• 批准号: 7099499
• 负责人: KAREN A. FAGAN
• 金额: $ 11.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099499
• 关键词: disease /disorder etiology; gel mobility shift assay; gene expression; hypoxia; idiopathic pulmonary fibrosis; immunocytochemistry; laboratory mouse; laboratory rat; medical complication; microarray technology; nitric oxide synthase; nitrogen oxides; oxidative stress; peroxynitrites; polymerase chain reaction; pulmonary circulation; pulmonary hypertension; respiratory oxygenation; sleep apnea; superoxide dismutase; transcription factor; vascular resistance; western blottings

DESCRIPTION (provided by applicant): Pulmonary hypertension (PHTN) is common in diseases characterized by chronic hypoxia (CH) (i.e. COPD, IPF) and occurs in 15-40% of patients with sleep apnea. Intermittent hypoxia (IH) mimicking the hypoxia-reoxygenation cycles of sleep apnea causes systemic hypertension and altered regulation of systemic vascular tone. However, the effect of intermittent hypoxia on the pulmonary circulation is unknown. Recently, patients with sleep apnea-induced PHTN were found to have exaggerated hypoxic pulmonary vasoconstriction. Unlike in chronic hypoxia, hypoxia in sleep apnea is not continuous, thus the mechanisms causing sleep apnea-induced PHTN are likely different from chronic hypoxia-induced PHTN. We therefore hypothesize that intermittent hypoxia leads to pulmonary hypertension by differential expression of genes important in regulating pulmonary vascular tone. Specifically, we hypothesize that oxidant stress in IH increases NOS and decreases SOD leading to PHTN through increased formation of peroxynitrite thus decreasing NO available for cellular effects such as attenuating vasoconstriction and mediating vasodilation. We further hypothesize that IH activates redox sensitive transcription factors leading to differential lung gone expression compared to CH. We will present data showing IH-induced PHTN in both rats and mice. We also will present data showing differential expression of NOS (nitric oxide synthase) and SOD (superoxide dismutase) in the lung following IH compared to CH, which may contribute to IH-induced PHTN through increased oxidant stress and decreased NO activity. This proposal will address the questions: 1) does repetitive hypoxia-reoxygenation causes pulmonary hypertension, 2) that despite increased NOS, NO appears to be insufficient to prevent IH-induced PHTN, 3) decreased SOD may contribute to IH-induced PHTN by increasing oxidant stress and formation of peroxynitrite, and 4) does IH leads to differential gene expression through activation of specific signaling pathways compared to CH. We will correlate physiologic measures of PHTN and pulmonary vascular tone with expression and activity of NOS and SOD, measurements of oxidant stress and NO, and activation of specific signaling pathways leading to altered gone expression in IH. This proposal, for the first time, will identify the consequences of IH in the pulmonary circulation. Understanding mechanisms contributing to the development of PHTN in IH may lead improved cardiovascular morbidity and mortality in this common disease.

描述（由申请人提供）：肺动脉高压（PHTN）常见于以慢性缺氧（CH）为特征的疾病（即COPD， IPF），发生在15-40%的睡眠呼吸暂停患者中。间歇性缺氧（IH）模仿睡眠呼吸暂停的缺氧-再氧循环导致全身性高血压和全身血管张力调节的改变。然而，间歇性缺氧对肺循环的影响尚不清楚。最近，睡眠呼吸暂停引起的PHTN患者被发现有严重的缺氧性肺血管收缩。与慢性缺氧不同，睡眠呼吸暂停的缺氧不是持续的，因此睡眠呼吸暂停诱导PHTN的机制可能与慢性缺氧诱导的PHTN不同。因此，我们假设间歇性缺氧通过调节肺血管张力的重要基因的差异表达导致肺动脉高压。具体来说，我们假设IH中的氧化应激增加NOS并减少SOD，通过增加过氧亚硝酸盐的形成导致PHTN，从而减少可用于细胞作用的NO，如减弱血管收缩和介导血管舒张。我们进一步假设IH激活氧化还原敏感转录因子，导致与CH不同的肺gone表达。我们将展示IH在大鼠和小鼠中诱导PHTN的数据。我们还将提供的数据显示，与CH相比，IH后肺中NOS（一氧化氮合酶）和SOD（超氧化物歧化酶）的表达差异，这可能通过氧化应激增加和NO活性降低来促进IH诱导的PHTN。本建议将处理下列问题：1)重复缺氧-再氧合是否会导致肺动脉高压？ 2)尽管NOS增加，NO似乎不足以预防ih诱导的PHTN。3)SOD的降低可能通过增加氧化应激和过氧亚硝酸盐的形成来促进ih诱导的PHTN。4)与CH相比，IH是否通过激活特定信号通路导致差异基因表达。我们将把PHTN和肺血管张力的生理测量与NOS和SOD的表达和活性、氧化应激和NO的测量以及导致IH中gone表达改变的特定信号通路的激活联系起来。这一建议将首次确定IH在肺循环中的后果。了解促进IH中PHTN发展的机制可能会改善这种常见疾病的心血管发病率和死亡率。