Genetic and Molecular Mechanisms in Hypoxia-Induced Pulmonary Hypertension

缺氧性肺动脉高压的遗传和分子机制

• 批准号: 8001415
• 负责人: Jason X J Yuan
• 金额: $ 37.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001415
• 关键词: Acute; Affect; Binding; Candidate Disease Gene; Cardiac; Chronic; DNA Binding; Data; Development; Drosophila melanogaster; Etiology; Gene Expression; Gene Expression Regulation; Genes; Goals; Heart; Heart failure; Human; Hypertension; Hypoxia; Knock-out; Molecular; Molecular Genetics; Notch Signaling Pathway; Pulmonary Hypertension; Right-On; Smooth Muscle; Ventricular; fly; hemodynamics; human subject; metabolomics; pulmonary arterial hypertension

Hypoxia-induced pulmonary hypertension (HPH) is a condition that increases mortality in patients with cardiopulmonary diseases (e.g., chronic obstructive pulmonary disease, COPD) and obstructive sleep apnea. Multifactorial etiology involving abnormalities in pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells has been implicated in HPH. Our data demonstrate that a) hypoxia upregulates NotchS in lung fissues and PASMC; b) hypoxia-induced pulmonary vascular remodeling is inhibited in Notch3 knockout mice; and c) Jaggedl, NotchS and Hes5 are all upregulated in lung fissues and PASMC from pafients with PH compared with normal subjects and normotensive patients. Furthermore, our observations indicate that: /) hypoxia upregulates TRP channels and increases AP-1 binding activity in PAEC; /¿/) hypoxia inhibits Kv channels in PASMC; and ///} Kv channel activity is decreased whereas TRP channel acfivity is increased in PASMC from PH patients compared with PASMC from normotensive subjects. These data imply that Notch signaling may interact with ion channels (e.g., Kv and TRP channels) and other signal transducfion cascades in regulafing pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in animals and pafients with HPH. The goal of this study is to determine whether and how Notch signaling, by interacting with hypoxia-sensitive membrane channels, is involved in a) the inifiafion and progression of HPH and b) the variability of pulmonary vascular suscepfibility to hypoxia. The central hypotheses are that /) selective Notch signaling genes and ion channels in PASMC/PAEC are involved in hypoxia-mediated changes in pulmonary vascular funcfion/structure and //) differenfial regulafion of these genes (i.e., expression and function) by hypoxia in PASMC/PAEC determines hypoxia susceptibility. Three Specific Aims are proposed in this project: 1) To characterize the effects of acute, intermittent and sustained hypoxia on the expression and function of genes in the Notch signaling pathway and genes encoding Kv and TRP channels in normal PASMC and PAEC from humans and mice; 2) To determine and compare the expression and function of genes in the Notch signaling pathway and genes encoding Kv and TRP channels in PASMC and PAEC isolated from normoxic control mice and HPH mice; and 3) To determine and compare expression and funcfion of genes in the Notch signaling pathway and Kv and TRP channels in PASMC and PAEC isolated from /) normotensive pafients, ii) COPD patients with HPH, iii) COPD pafients without HPH, and iv) pafients with pulmonary arterial hypertension.

缺氧诱导的肺动脉高压（HPH）是一种增加患者死亡率的疾病， 心肺疾病（例如，慢性阻塞性肺疾病（COPD）和阻塞性睡眠 呼吸暂停涉及肺动脉平滑肌（PASMC）异常的多因素病因， 内皮细胞（PAEC）与HPH有关。我们的数据表明，a）缺氧上调 B）肺裂和PASMC中的NotchS; c）Jaggedl、NotchS和Hes 5在肺裂和PASMC中均上调 与正常人和正常血压患者比较。而且我们的 观察表明：/）缺氧上调TRP通道并增加AP-1结合活性， PAEC; //）缺氧抑制PASMC中的Kv通道;和/} Kv通道活性降低，而TRP 与正常血压者相比，PH患者PASMC的通道活性增加 科目这些数据暗示Notch信号传导可以与离子通道（例如，Kv和TRP通道） 和其他信号转导级联在调节肺血管重构中的作用，这是肺血管重构的主要原因。 HPH动物和患者肺血管阻力升高。本研究的目的是 确定Notch信号是否以及如何通过与缺氧敏感膜通道相互作用， 参与a）HPH的发生和进展和B）肺血管通透性的变异性 缺氧。中心假设是：1）选择性Notch信号传导基因和离子通道在细胞中表达。 PASMC/PAEC参与低氧介导的肺血管功能/结构的改变和//） 这些基因的差异调节（即，PASMC/PAEC中缺氧的表达和功能）决定 缺氧敏感性本项目提出了三个具体目标：1）表征 急性、间歇性和持续性缺氧对Notch信号通路中基因表达和功能的影响 人和小鼠正常PASMC和PAEC中编码Kv和TRP通道的通路和基因; 2） 确定并比较Notch信号通路中基因的表达和功能， 编码从常氧对照小鼠和HPH小鼠分离的PASMC和PAEC中的Kv和TRP通道; 和3）确定和比较Notch信号通路中基因的表达和功能以及Kv 和TRP通道，i）正常血压患者，ii）患有HPH的COPD患者， iii）没有HPH的COPD患者，和iv）具有肺动脉高压的患者。