Biochemical and Metabolic Properties of 20-HETE

描述(申请人提供)：20-羟基二十碳四烯酸(20-HETE)是一种二十烷基类生物介体，由花生四烯酸通过细胞色素P450 omega-氧化酶合成。20-HETE产生血管收缩，刺激有丝分裂，还调节肾小管中的离子运输。越来越多的证据表明，这些作用在包括高血压和中风在内的主要心血管疾病的病理生理学中发挥着重要作用。本项目的目的是从细胞水平和酶水平研究20-HETE的生化和代谢特性。这将补充现有的生理和药理学信息，并提供对20-HETE如何对心血管系统产生有害影响的更完整的了解。有三个具体目标。目的1研究20-HETE在血管内皮细胞和血管平滑肌细胞中的掺入、转运、滞留和代谢，以确定其功能作用和有害心血管作用的生化基础。目的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。它将包括对酒精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一代谢过程的假设，从而延长20-HETE在血管系统中的病理效应。目的3将验证补充omega-3多不饱和脂肪酸是减少20-HETE的产生从而减少其在心血管系统中的病理作用的有效手段的假设。这将包括细胞色素P450 omega-oxase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20-HETE的细胞和生化作用。该项目的最终目标是提供必要的额外机制洞察力，以开发新的治疗方法来克服20-HETE的病理作用。

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.