Pulmonary Hypertension following Intermittent Hypoxia

描述(申请人提供)：肺动脉高压(PHTN)常见于以慢性低氧(CH)为特征的疾病(即COPD，IPF)，并出现在15%-40%的睡眠呼吸暂停患者中。间歇性低氧(IH)模拟睡眠呼吸暂停的低氧-复氧循环，导致全身性高血压和全身血管张力调节的改变。然而，间歇性低氧对肺循环的影响尚不清楚。最近，睡眠呼吸暂停所致的PHTN患者被发现有过度的缺氧性肺血管收缩。与慢性低氧不同，睡眠呼吸暂停中的低氧不是持续性的，因此睡眠呼吸暂停诱发PHTN的机制可能不同于慢性低氧诱导的PHTN。因此，我们假设间歇性低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。具体地说，我们假设IH的氧化应激增加了NOS，降低了SOD，通过增加过氧亚硝酸盐的形成而导致PHTN，从而减少了可用于细胞效应的NO，如减弱血管收缩和介导血管扩张。我们进一步假设，与CH相比，IH激活了氧化还原敏感的转录因子，导致了不同的肺GO表达。我们将提供数据显示IH在大鼠和小鼠中诱导的PHTN。我们还将提供的数据显示，与CH相比，IH后肺组织中NOS(一氧化氮合酶)和SOD(超氧化物歧化酶)的表达存在差异，这可能通过增加氧化应激和降低NO活性来参与IH诱导的PHTN。这一建议将解决以下问题：1)反复低氧-复氧是否导致肺动脉高压；2)尽管NOS升高，但NO似乎不足以阻止IH诱导的PHTN；3)降低的SOD可能通过增加氧化应激和过氧亚硝酸盐的形成而参与IH诱导的PHTN；以及4)IH是否通过激活特定的信号通路而导致与CH相比的差异基因表达。我们将PHTN和肺血管张力的生理指标与NOS和SOD的表达和活性、氧化应激和NO的测量以及导致IH GONE表达改变的特定信号通路的激活相关联。这项提案将首次确定IH对肺循环的影响。了解在IH中导致PHTN发生的机制可能有助于改善这种常见疾病的心血管发病率和死亡率。

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.