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.
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