Biochemical and Metabolic Properties of 10-HETE

10-HETE 的生化和代谢特性

• 批准号: 6719071
• 负责人: ARTHUR A. SPECTOR
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-10 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719071
• 关键词: alcohol dehydrogenase; cardiovascular injury; cytochrome P450; eicosanoid metabolism; eicosanoids; ethanol; inhibitor /antagonist; molecular pathology; omega 3 fatty acid; tissue /cell culture; vascular endothelium; vascular smooth muscle

DESCRIPTION (provided by applicant): 20-Hydroxyeicosatetraenoic acid (20-HETE) is an eicosanoid biomediator synthesized from arachidonic acid by cytochrome P450 omega-oxidases. 20-HETE produces vasoconstriction, it stimulates mitogenesis, and it also modulates ion transport in the renal tubule. There is increasing evidence that these actions play an important role in the pathophysiology of major cardiovascular diseases, including hypertension and stroke. The objective of this project is to investigate the biochemical and metabolic properties of 20-HETE at the cellular and enzymatic level. This will complement the existing physiologic and pharmacologic information and provide a more complete understanding of how 20-HETE produces its deleterious effects on the cardiovascular system. There are three Specific Aims. Aim 1 will investigate the incorporation, trafficking, retention, and metabolism of 20-HETE in endothelial and vascular smooth muscle cells, with the objective of determining the biochemical basis for its functional effects and harmful cardiovascular actions. Aim 2 will determine the mechanism through which 20-HETE is converted to its major metabolite, 20-carboxyarachidonic acid. It will include an evaluation of the role of alcohol dehydrogenases in this conversion, and it will test the hypothesis that ethanol may inhibit this metabolic process and thereby prolong the pathological effects of 20-HETE in the vascular system. Aim 3 will test the hypothesis that omega-3 polyunsaturated fatty acid supplementation is an effective means for reducing the production of 20-HETE and thereby decreasing its pathological actions in the cardiovascular system. This will include a determination of whether cytochrome P450 omega-oxidases can convert eicosapentaenoic acid (EPA), the omega-3 polyunsaturated fatty acid analogue of arachidonic acid, to 20-hydroxy-EPA, and whether this EPA-derivative will inhibit the cellular and biochemical actions of 20-HETE. The ultimate goal of this project is to provide the additional mechanistic insight necessary to develop new therapeutic approaches to overcome the pathological actions of 20-HETE.

描述（由申请人提供）：20-羟基二十碳四烯酸（20-HETE）是一种类二十烷酸生物介质，由细胞色素 P450 omega-氧化酶从花生四烯酸合成。 20-HETE 产生血管收缩作用，刺激有丝分裂，还调节肾小管中的离子转运。越来越多的证据表明，这些作用在主要心血管疾病（包括高血压和中风）的病理生理学中发挥着重要作用。该项目的目的是在细胞和酶水平上研究 20-HETE 的生化和代谢特性。这将补充现有的生理学和药理学信息，并提供对 20-HETE 如何对心血管系统产生有害影响的更全面的了解。共有三个具体目标。目标 1 将研究 20-HETE 在内皮和血管平滑肌细胞中的掺入、运输、保留和代谢，目的是确定其功能影响和有害心血管作用的生化基础。目标 2 将确定 20-HETE 转化为其主要代谢物 20-羧基花生四烯酸的机制。它将包括对乙醇脱氢酶在这种转化中的作用的评估，并将检验乙醇可能抑制这种代谢过程并从而延长 20-HETE 在血管系统中的病理作用的假设。目标 3 将检验以下假设：补充 omega-3 多不饱和脂肪酸是减少 20-HETE 产生的有效手段，从而减少其在心血管系统中的病理作用。这将包括确定细胞色素 P450 omega-氧化酶是否可以将二十碳五烯酸 (EPA)（花生四烯酸的 omega-3 多不饱和脂肪酸类似物）转化为 20-羟基-EPA，以及这种 EPA 衍生物是否会抑制细胞和20-HETE 的生化作用。该项目的最终目标是提供必要的额外机制见解，以开发新的治疗方法来克服 20-HETE 的病理作用。