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），并且发生在15-40%的睡眠呼吸暂停患者中。 间歇性缺氧（IH）类似于睡眠呼吸暂停的缺氧-复氧循环，会导致全身性高血压并改变全身血管张力的调节。 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 患者被发现存在过度的缺氧性肺血管收缩。 与慢性缺氧不同，睡眠呼吸暂停中的缺氧不是连续的，因此导致睡眠呼吸暂停诱发的 PHTN 的机制可能与慢性缺氧诱发的 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而导致肺动脉高压。 具体来说，我们假设 IH 中的氧化应激会增加 NOS 并减少 SOD，通过增加过氧亚硝酸盐的形成而导致 PHTN，从而减少可用于细胞作用（例如减弱血管收缩和介导血管舒张）的 NO。 我们进一步假设 IH 激活氧化还原敏感转录因子，导致与 CH 相比肺表达差异。 我们将提供显示 IH 在大鼠和小鼠中诱导 PHTN 的数据。 我们还将提供显示与 CH 相比 IH 后肺部 NOS（一氧化氮合酶）和 SOD（超氧化物歧化酶）差异表达的数据，这可能通过增加氧化应激和降低 NO 活性而导致 IH 诱导的 PHTN。 该提案将解决以下问题：1）重复缺氧-复氧是否会导致肺动脉高压，2）尽管 NOS 增加，但 NO 似乎不足以预防 IH 诱导的 PHTN，3）SOD 减少可能通过增加 IH 诱导的 PHTN 来促进 IH 诱导的 PHTN氧化应激和过氧亚硝酸盐的形成，4) 与 CH 相比，IH 是否通过激活特定信号通路导致基因表达差异。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。 该提案将首次确定 IH 对肺循环的影响。了解 IH 中 PHTN 发生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。