Role of Hypoxia Inducible Factor-1 in Inflammation

缺氧诱导因子 1 在炎症中的作用

• 批准号: 6925895
• 负责人: ALPHA Alsbury FOWLER
• 金额: $ 37.25万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-09 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925895
• 关键词: RNA interference; carbon monoxide; enzyme induction /repression; enzyme linked immunosorbent assay; gene expression; genetic promoter element; genetically modified animals; heme oxygenase; hypoxia inducible factor 1; inflammation; interleukin 8; intermolecular interaction; laboratory mouse; myocardial ischemia /hypoxia; nitric oxide; nitric oxide synthase; oxidative stress; polymerase chain reaction; protein structure function; reperfusion; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Biological processes occurring in post-ischemic vasculature commonly initiate events that produce failure of endogenous inflammatory systems, precipitating vascular and parenchymal organ injury. Hypoxia Inducible Factor-1 (HIF-1), a heterodimeric protein consisting of alpha and beta subunits activated in vascular endothelium during hypoxia, modulates expression of genes essential for cell survival (i.e., inducible nitric oxide synthase and heme oxygenase-1) in ischemic environments. Little research to date has established a role for HIF-1 in modulating inflammatory events that occur in post ischemic vasculature. New research leading to submission of this revised application reveals that stabilization of the alpha subunit of HIF-1 dramatically reduces infarct size and polymorphonuclear neutrophil infiltration in post-ischemic rabbit and murine hearts, lnterleukin-8 (IL-8), a pro-inflammatory chemokine consistently associated with post-ischemic vascular injury and organ damage was strikingly repressed by HIF-1 activation in our studies. In vitro experiments using human microvascular endothelial cells suggest that HIF-1 modulates secretion of IL-8 acting directly at a transcriptional level or indirectly through generation of nitric oxide (NO) and carbon monoxide (CO) following induction of nitric oxide synthase and heme oxygenase-1 (HO-1) genes respectively. We hypothesize that: Hypoxia inducible factor-1 acting independently or in concert with key effector genes regulates chemokine expression in reoxygenating microvascular endothelium. Four aims are proposed in this application: (1) To determine the role of HIF-1 activation in attenuation of cardiac chemokine generation following ischemia/reperfusion; (2) To examine molecular interdependency between NO and CO in regulation of IL-8 expression in reoxygenating microvascular endothelium; (3) To evaluate the role of HIF-1 in modulating HO-1-induced IL-8 generation; (4) To determine the functional significance of IL-8 promoter binding by HIF-1 in microvascular endothelium. The research proposed here will produce substantial new knowledge, establishing HIF-1 as a pivotal molecule in modulation of inflammatory events. Further, the results of this work will open a new era of understanding of the regulation of chemokine induced inflammation and permit the rational design of tools targeted specifically to attenuate post-ischemic vascular injury.

描述（由申请人提供）：缺血后脉管系统中发生的生物过程通常会引发导致内源性炎症系统衰竭的事件，从而加速血管和实质器官损伤。缺氧诱导因子-1 (HIF-1) 是一种异二聚体蛋白，由缺氧期间在血管内皮中激活的 α 和 β 亚基组成，可调节缺血环境中细胞生存必需的基因（即诱导型一氧化氮合酶和血红素加氧酶-1）的表达。迄今为止，很少有研究证实 HIF-1 在调节缺血后脉管系统中发生的炎症事件中的作用。导致提交此修订申请的新研究表明，HIF-1 α亚基的稳定可显着减少缺血后兔和小鼠心脏中的梗死面积和多形核中性粒细胞浸润，白介素 8 (IL-8)（一种与缺血后血管损伤和器官损伤一致相关的促炎趋化因子）受到显着抑制 我们研究中的 HIF-1 激活。使用人微血管内皮细胞的体外实验表明，HIF-1 在转录水平上直接调节 IL-8 的分泌，或在分别诱导一氧化氮合酶和血红素加氧酶-1 (HO-1) 基因后通过产生一氧化氮 (NO) 和一氧化碳 (CO) 间接调节 IL-8 的分泌。我们假设：缺氧诱导因子 1 独立作用或与关键效应基因协同作用调节微血管内皮复氧中趋化因子的表达。本申请提出了四个目标：(1)确定HIF-1激活在缺血/再灌注后减弱心脏趋化因子产生中的作用； (2) 研究NO和CO在调节微血管内皮复氧中IL-8表达中的分子相互依赖性； (3)评价HIF-1在调节HO-1诱导的IL-8生成中的作用； (4)确定HIF-1结合IL-8启动子在微血管内皮细胞中的功能意义。这里提出的研究将产生大量新知识，将 HIF-1 确立为调节炎症事件的关键分子。此外，这项工作的结果将开启理解趋化因子诱导的炎症调节的新时代，并允许合理设计专门用于减轻缺血后血管损伤的工具。