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: 7174232
• 负责人: ALPHA Alsbury FOWLER
• 金额: $ 35.32万
• 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/7174232
• 关键词: Acute; Adhesions; Antioxidants; Attenuated; Binding; Biological; Biological Process; Blood Circulation; Blood Vessels; Carbon Monoxide; Cardiac; Cell Survival; Cellular Stress; Cessation of life; Condition; Employee Strikes; Endothelial Cells; Endothelium; Environment; Essential Genes; Event; Exhibits; Failure; Generations; Genes; Genetic; HIF1alpha protein; Heart; Hemin; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Iron; Ischemia; Knowledge; Laboratories; Maintenance; Modeling; Molecular; Mus; Myocardial; Myocardium; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase; Nitrogen; Organ; Oryctolagus cuniculus; Oxidants; Oxygen; Physiological reperfusion; Play; Procollagen-Proline Dioxygenase; Protein Isoforms; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Repression; Research; Research Personnel; Role; Stress; System; Testing; Vascular Endothelial Cell; Vascular Endothelium; Work; attenuation; chemokine; design; heme oxygenase-1; human NOS2A protein; hypoxia inducible factor 1; in vivo; in vivo Model; migration; myocardial infarct sizing; neutrophil; promoter; protoporphyrin IX; research study; size; tool; vascular bed

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（由申请方提供）：缺血后血管系统中发生的生物学过程通常会引发导致内源性炎症系统衰竭的事件，从而导致血管和实质器官损伤。缺氧诱导因子-1（HIF-1）是一种由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，其调节细胞存活所必需的基因的表达（即，诱导型一氧化氮合酶和血红素氧合酶-1）。迄今为止，很少有研究确定了HIF-1在调节缺血后血管系统中发生的炎症事件中的作用。导致提交该修订申请的新研究表明，HIF-1的α亚基的稳定化显著降低缺血后兔和小鼠心脏中的梗死面积和多形核白细胞中性粒细胞浸润。在我们的研究中，HIF-1活化显著抑制了白细胞介素-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。使用人微血管内皮细胞的体外实验表明，HIF-1调节IL-8的分泌，其直接在转录水平起作用，或通过分别诱导一氧化氮合酶和血红素加氧酶-1（HO-1）基因后产生一氧化氮（NO）和一氧化碳（CO）而间接起作用。我们假设：缺氧诱导因子-1独立或与关键效应基因协同作用调节再氧微血管内皮中趋化因子的表达。本申请提出了四个目的：（1）确定HIF-1激活在缺血/再灌注后心脏趋化因子产生减弱中的作用;（2）检测NO和CO在调节再氧微血管内皮细胞中IL-8表达中的分子相互依赖性;（3）评估HIF-1在调节HO-1诱导的IL-8产生中的作用;（4）探讨HIF-1与IL-8启动子结合在微血管内皮细胞中的功能意义。这项研究将产生大量的新知识，建立HIF-1作为调节炎症事件的关键分子。此外，这项工作的结果将打开一个新时代的理解趋化因子诱导的炎症的调节，并允许合理设计的工具，专门针对减轻缺血后血管损伤。