• Knapp, Howard (PI)
  • Chappell, David (PI)
  • Weintraub, Neal Lee (PI)
  • Spector, Arthur (PI)
  • Spector, Arthur (PI)
  • Chappell, David (PI)

Project: Research project

Project Details


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.
Effective start/end date9/30/928/31/03


  • Medicine(all)