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: 7015643
• 负责人: ALPHA Alsbury FOWLER
• 金额: $ 36.37万
• 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/7015643
• 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）：在缺血后血管中发生的生物过程通常会引发导致内源性炎症系统失败，导致血管和实质器官损伤的事件。低氧诱导因子1（HIF-1），一种在缺氧期间在血管内皮中激活的α和β亚基组成的异二聚体蛋白，调节细胞存活所必需的基因表达（即，在缺血性氧化物合酶和血清氧酶1）中所必需的基因表达环境。迄今为止，很少有研究确定了HIF-1在调节缺血性脉管系统中发生的炎症事件中的作用。新的研究导致提交这项修订的应用程序表明，HIF-1的Alpha亚基稳定会大大降低梗死的大小和多形核中性粒细胞浸润后缺血后兔子和鼠心，Lnterleukin-8（IL-8）在我们的研究中，HIF-1激活使与缺血后血管损伤和器官损伤相关的趋化因子始终如一。使用人类微血管内皮细胞的体外实验表明，HIF-1通过诱导一氧化氮氧化物合成酶和血红素氧化酶后，通过产生一氧化氧化物（NO）和一氧化碳（CO）来调节直接在转录水平或间接作用的IL-8的分泌。 -1（HO-1）基因。我们假设这是：缺氧诱导因子1独立作用或与关键效应基因一起起作用，可调节微血管内皮的重氧化因子表达。在本应用中提出了四个目标：（1）确定HIF-1激活在缺血/再灌注后心脏趋化因子产生衰减中的作用； （2）检查NO和CO之间的分子相互依赖性在调节重氧微血管内皮中IL-8表达的调节中； （3）评估HIF-1在调节HO-1诱导的IL-8生成中的作用； （4）确定HIF-1在微血管内皮中的IL-8启动子结合的功能显着性。这里提出的研究将产生大量的新知识，将HIF-1确立为炎症事件调节中的关键分子。此外，这项工作的结果将为趋化因子诱导的炎症调节的新时代开辟一个新时代，并允许专门针对减轻缺血后血管损伤的工具的合理设计。