This is an amended application examining mechanisms by which xenobiotics may promote atherosclerosis. The proposal focuses on prostaglandin synthase 2 (PGS-2), an early response gene that regulates prostaglandin synthesis. PGS-2 has both cyclooxygenase and peroxidase activity. Only the cyclooxygenase activity is inhibited by NSAIDs. It is hypothesized that stimulation of PGS-2 synthesis in the smooth muscle and endothelial cells of injured vessels may lead to the production of toxic metabolites which stimulate atherosclerosis and carcinogenesis. The failure of NSAIDs to inhibit atherosclerosis may in part be due to their inability to block the peroxidase activity of PGS-2. In contrast, retinoids, which block PGS-2 transcription, may be more effective.
Aim 1 will determine if induction of PGS-2 in vascular tissue promotes xenobiotic transformation to products that alter DNA, increase cell proliferation, and further upregulate PGS-2. Benzo(a)pyrene (B[a]P) will be used as a prototype xenobiotic polycyclic aromatic hydrocarbon (PAH). Studies will employ smooth muscle and endothelial cell culture, ex vivo culture of human arteries, and in vivo models of arterial injuries.
Aim 2 will investigate if increased vascular PGS-2 promotes the formation of arachidonate metabolites that contribute to vascular smooth muscle cell proliferation. Emphasis will be placed on the effects of aspirin and increased 15-HETE production.
Aim 3 will elucidate the mechanisms by which retinoids decrease induction of PGS-2 in the vessel wall and inhibit prostaglandin production and will assess the effects of retinoids on mechanical or B[a]P-induced vascular injury. These studies are designed to elucidate the mechanisms involved in a novel pathologic interaction between inflammation and xenobiotic processing in the vascular wall and may lead to new approaches to attenuate vascular proliferation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055627-04
Application #
6184022
Study Section
Pathology A Study Section (PTHA)
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2000
Total Cost
$332,196
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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