Formation of Omega 3-Derived Electrophiles During Inflammation

炎症过程中 Omega 3 衍生的亲电子试剂的形成

基本信息

批准号：
8195180
负责人：
Francisco Jose Schopfer
金额：
$ 37.88万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195180
关键词：
Accounting Acute Address Anabolism Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Arachidonate 15-Lipoxygenase Arterial Fatty Streak Aspirin Asses Atherosclerosis Biochemical Biological Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Cell model Cells Cessation of life Clinical Research Cytochrome P450 Cytoprotection Data Development Diet Disease Endothelial Cells Enzymes Event Family member Fatty Acids Fatty acid glycerol esters Fish Oils Foundations Gene Expression Generations Glutathione Health Homeostasis Human In Vitro Inflammation Inflammatory Inflammatory Response Isoenzymes Knockout Mice Label Lead Lipids Lipoxygenase Low Density Lipoprotein Receptor Macrophage Activation Maps Measures Mediating Mediator of activation protein Modeling Molecular Target Mus Nature Omega-3 Fatty Acids Oxidoreductase Pathway interactions Peritonitis Phase Physiological Plasma Polyunsaturated Fatty Acids Property Proteins Pump Reaction Reagent Regulation Research Resolution Signal Pathway Signal Transduction Smooth Muscle Myocytes Solid Structure Testing Tissues United States Zymosan adduct analytical tool animal tissue cell type cyclooxygenase 2 cytokine design enzyme substrate feeding human NOS2A protein improved in vivo in vivo Model macrophage neutrophil novel oxidation reaction rate stem vascular bed

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis accounts for three fourth of all deaths from cardiovascular disease and atherothrombotic diseases are projected to be the leading cause of death worldwide in 2020, representing a major health burden. Omega-3 (w-3) polyunsaturated fatty acids exert potent anti-inflammatory actions and beneficial cardiovascular effects. Although these properties are widely recognized, the underlying mechanisms remain largely unknown. An electrophilic mapping of lipids formed during macrophage activation showed that keto-derived w-3 fatty acids omega 3 derived-fatty acids were present at intracellular concentrations up to 200 nM. The formation of these species was dependent on COX-2, and administered aspirin increased the levels of these w-3 electrophilic fatty acid oxo-derivatives (EFOX). Recently, EFOX have been shown to be formed in human macrophages, neutrophils and animal tissues subjected to inflammation. Additionally, EFOX have been found to form glutathione and protein adducts and to modulate the inflammatory pathways through activation of Nrf2 pathway, inhibition of cytokine expression and reduction of inducible nitric oxide synthase levels. The hypothesis of this proposal is that EFOX are biologically relevant molecules with anti-atherogenic properties formed during inflammation and atherosclerosis that transduce the beneficial effects of w-3 fatty acids and aspirin through the electrophilic regulation of signaling pathways. To address this hypothesis we propose to chemically generate analytical tools (i.e. deuterated and labeled standards) to aid in the rigorous biological identification and quantitation of EFOX. These standards will be used for the analysis of biosynthetic pathways in macrophages and to assess the in vivo formation in a relevant murine model of atherosclerosis. The biochemical and signaling properties of these species and its targets will be analyzed using cellular models. Finally, the pharmacological effects of EFOX will be tested on a murine atherosclerosis model. At completion, we expect to have determined the different EFOX isomeric species and their in vivo relevance and formation. In addition, we expect to have gained a clear understanding of their electrophilic reactivities, modulation of phase 2 gene expression, in particular the Nrf2/KEAP1 pathway and their PPARg activation. It is expected that this proposal will lead to a better understanding of w-3 fatty acid effects and to improved pharmacological approaches to decrease atherosclerosis and its detrimental effects. PUBLIC HEALTH RELEVANCE: Atherosclerosis is responsible for over 500,000 deaths per year in the United States. Omega-3 polyunsaturated fatty acids, commonly found in fish oil, exert potent anti-inflammatory actions and beneficial cardiovascular effects although the operative mechanisms remain largely unknown. We recently discovered the formation of novel anti-inflammatory lipids called EFOX by human macrophages and neutrophils during inflammation. We propose to characterize the biochemical functionalities of these species and their effects and levels during atherosclerosis. It is expected that the results will not only increase our understanding of this disease, but also allow for a better design of pharmacological approaches for its treatment.

描述（由申请人提供）：动脉粥样硬化占心血管疾病和动脉粥样硬化性疾病的所有死亡的四分之三，预计将在2020年全球死亡的主要原因，代表了重大的健康负担。 omega-3（W-3）多不饱和脂肪酸发挥有效的抗炎作用和有益的心血管效应。尽管这些特性得到了广泛认可，但潜在的机制仍然在很大程度上未知。在巨噬细胞激活过程中形成的脂质的亲电图表明，酮衍生的W-3脂肪酸欧米茄3衍生的脂肪酸存在于高达200 nm的细胞内浓度。这些物种的形成取决于COX-2，并且给药阿司匹林增加了这些W-3亲电脂肪酸氧衍生物（EFOX）的水平。最近，EFOX已显示出在人类巨噬细胞，中性粒细胞和受炎症的动物组织中形成。另外，已经发现EFOX形成谷胱甘肽和蛋白质加合物，并通过激活NRF2途径，抑制细胞因子表达和降低诱导型一氧化氮合酶水平来调节炎症途径。该提议的假设是，EFOX是在炎症和动脉粥样硬化期间形成的抗动脉粥样硬化特性的生物学相关分子，可通过信号通路的亲电调节W-3脂肪酸和阿司匹林传递W-3脂肪酸和阿司匹林的有益作用。为了解决这一假设，我们提出了化学生成分析工具（即还是往的标准标准），以帮助对EFOX的严格生物学识别和定量。这些标准将用于分析巨噬细胞中的生物合成途径，并评估动脉粥样硬化相关的鼠模型中的体内形成。这些物种及其靶标的生化和信号传导特性将使用细胞模型进行分析。最后，将在鼠动脉粥样硬化模型上测试EFOX的药理作用。完成后，我们预计将确定不同的EFOX同类物种及其体内相关性和形成。此外，我们期望对它们的亲电反应率有清晰的了解，对2期基因表达的调节，特别是NRF2/KEAP1途径及其PPARG激活。可以预期，该提案将更好地了解W-3脂肪酸效应，并改善药理学方法以减少动脉粥样硬化及其有害作用。公共卫生相关性：在美国，动脉粥样硬化每年造成500,000多人死亡。 omega-3多不饱和脂肪酸，通常在鱼油中发现，发挥有效的抗炎作用和有益的心血管效应，尽管手术机制仍然在很大程度上未知。最近，我们发现了人类巨噬细胞和嗜中性粒细胞在炎症过程中形成的新型抗炎脂质，称为EFOX。我们建议表征这些物种的生化功能及其在动脉粥样硬化期间的作用和水平。预计结果不仅会增加我们对这种疾病的理解，而且还可以更好地设计其治疗的药理学方法。