Project 1 deals with the effects of polyunsaturated fatty acids (PUFA) and their products on endothelial and arterial smooth muscle cell function. The objective is to determine the role of lipid biomediators and oxidation products derived from PUFA in vascular regulation and atherogenesis. There are five specific aims.
Aim 1 will delineate the function of peroxisomal beta-oxidation of arachidonic acid, and whether there is competition between different n-6 and n-3 PUFA for entry into this pathway. The function of two products produced from arachidonic acid by this pathway, 12:2n-6 and 16:3n-6, will be explored, as well as the extent to which this pathway operates in endothelial and smooth muscle cells and generates reactive oxygen species (ROS).
Aim 2 will examine the metabolism of PUFA oxidation products such as epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and hydroxyoctadecadienoic acids (HODEs) by the arterial cells. The handling of EETs by microvessel and large vessel endothelial cells will be compared. The hypothesis that these compounds generate ROS and can thereby trigger LDL oxidation will be tested, and the ability to protect against this by transfecting endothelial cells with antioxidant enzyme genes will be explored.
Aim 3 will investigate the mechanism by which EETs and other oxygenated arachidonic acid metabolites induce endothelial activation and the expression of leukocyte adhesion molecules, with emphasis on transcriptional and translational control.
Aim 4 will utilize patch clamping to test the hypothesis that exposure of smooth muscle to elevated amounts of PUFA, EETs, or related PUFA oxidation products affects Kplus channels, leading to changes in vascular reactivity.
Aim 5 will test the hypothesis that lipoprotein lipase induced lipolysis of triglyceride-rich lipoproteins and lipoproteins that contain oxidized lipids can adversely affect the function of endothelial cells. These data will provide basic new insight into the mechanisms by which PUFA and oxygenated PUFA products affect vascular functions that are involved in atherosclerosis and its complications.
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