The proposed research is based on the premise that oxidant stress, a potential consequence of inadequate selenium (Se) nutrition, can influence the synthesis of eicosanoids by endothelial cells. Selenium, in the form of selenocysteine, is an integral part of the active site of Se-dependent glutathione peroxidase (Se-GSH-Px), a key enzyme that protects cells by reducing intracellular hydrogen peroxide (H2O2) and fatty acid hydroperoxides (FAHP). The concentration of these peroxides, in turn, regulates the activities of cyclooxygenase (COX) and lipoxygenase (LOX) pathways, ultimately influencing the production of prostaglandins (PGs) and leukotrienes (LTs). Eicosanoids are involved intrinsically in the elaboration of autologous cytokines, platelet activating factor (PAF), and nitric oxide (NO) that are known to profoundly affect vascular integrity by influencing the balance between a proaggregating and antiaggregating state. Furthermore, increased H2O2 and FAHP levels during Se deficiency can act on signaling molecules to activate gene expression of a number of proinflammatory mediators, including vascular adhesion molecules. Thus, impaired Se status and Se-GSH-Px activity should have profound influence in the pathophysiology of atherosclerotic vascular diseases. The central hypothesis to be tested is that Se deficiency can influence the expression of key enzymes associated with PG and LT biosynthesis and thus, modify their product profiles in endothelial cells. This altered eicosanoid biosynthesis is, in part, responsible for the modified expression of critical effector molecules which influence vascular integrity and permeability. We propose to investigate the effects of altered Se nutrition on eicosanoid production in cultured bovine aortic endothelial cells and relate their biosynthesis to changes in endothelial cell effector molecule production and adhesion molecule expression at both the cellular and molecular level.
The Specific Aims are: 1) to determine the expression of COXs and LOXs as well as the product profiles of arachidonic acid cascade by way of their respective pathways in Se-deficient endothelial cells, 2) to evaluate the effects of Se deficiency on the production of such biological response modifiers as cytokines, PAF and NO in relation to altered eicosanoid production and 3) to evaluate the effects of altered eicosanoid production on the expression of adhesion molecules and endothelial cell permeability. Results form these studies will provide the molecular basis of how Se deficiency can modify resistance to metabolic vascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL060044-01A2
Application #
2902643
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Project Start
1999-07-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
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