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：
8891371
负责人：
Francisco Jose Schopfer
金额：
$ 36.37万
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/8891371
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 PPAR gamma 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 (ω-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 ω-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 ω-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 ω-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 PPARγ activation. It is expected that this proposal will lead to a better understanding of ω-3 fatty acid effects and to improved pharmacological approaches to decrease atherosclerosis and its detrimental effects.

描述（由申请人提供）：动脉粥样硬化占心血管疾病死亡人数的四分之三，预计到 2020 年，动脉粥样硬化将成为全球主要死亡原因，成为主要的健康负担。尽管这些特性已得到广泛认可，但巨噬细胞活化过程中形成的脂质的亲电图谱仍然未知。 ω-3 脂肪酸 omega 3 衍生脂肪酸在细胞内的浓度高达 200 nM。这些物质的形成依赖于 COX-2，服用阿司匹林会增加这些 ω-3 亲电脂肪酸含氧衍生物的水平。最近，EFOX 已被证明在遭受炎症的人类巨噬细胞、中性粒细胞和动物组织中形成。此外，还发现 EFOX 可以形成谷胱甘肽和该提议的假设是，EFOX 是在炎症和动脉粥样硬化过程中形成的具有抗动脉粥样硬化特性的生物学相关分子。通过信号通路的亲电子调节转导 ω-3 脂肪酸和阿司匹林的有益作用为了解决这一假设，我们建议以化学方式生成分析工具（即氘代和阿司匹林）。这些标准品将用于分析巨噬细胞中的生物合成途径，并评估相关小鼠动脉粥样硬化模型的体内形成情况。最后，我们将在小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 异构体种类及其作用。此外，我们期望对它们的亲电反应性、2相基因表达的调节，特别是 Nrf2/KEAP1 通路及其 PPARγ 激活有清晰的了解。更好地了解 ω-3 脂肪酸的作用，并改进减少动脉粥样硬化及其痛苦影响的药理学方法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of 10-Nitro Oleic Acid Bio-Elimination in Rats and Humans.

10-硝基油酸在大鼠和人类中的生物消除评估。

DOI：
发表时间：
2017-01-05
期刊：
影响因子：
4.6
作者：
Salvatore, Sonia R;Vitturi, Dario A;Fazzari, Marco;Jorkasky, Diane K;Schopfer, Francisco J
通讯作者：
Schopfer, Francisco J