Accumulation of cholesteryl ester and other lipids with macrophages, vascular smooth muscle cells (SMC) and the extracellular matrix is an early and persistent hallmark of the atherosclerotic lesion. Lipid accumulation is associated with the impairment of vascular relaxation mediated by prostacyclin (PGI2). We have demonstrated that cholesteryl ester-enrichment of arterial SMC, as occurs in atherosclerosis, alters eicosanoid production. The overall goal of this renewal application is to continue our studies to define the mechanisms by which foam cell development inhibits signaling pathways responsible for the generation of PGI2. In this revised proposal, we will advance our hypothesis that G-protein-mediated signaling processes involving cylooxygenase gene expression are altered in SMC-derived foam cells. The broad goal of this proposal is to define the relationship between low molecular weight and heterotrimeric G-protein assembly in arterial SMC, and to determine the impact of cholesterol-enrichment on this process. Experiments proposed in Aim 1 will test the hypothesis that cholesterol enrichment of SMC alters heterotrimeric G-protein content, assembly on cell membranes, and signaling.
In Aim 2, we will evaluate the mechanisms by which cell membrane cholesterol content alters electrostatic interactions between isoprenylated G-proteins, phospholipids and caveolae-associated signaling molecules resulting in the inhibition of G-proteins, phospholipids and caveolae-associated signaling molecules resulting in the inhibition of G-protein function. Finally, in Aim 3, we will assess the role of cholesterol-enrichment and oxygenated sterols on the inhibition of transcriptional and post-transcriptional regulation of cyclooxygenase-2 (COX-2). We believe that this revised proposal represents an integrated and focused approach to understanding the role of G-protein mediated signaling events in the regulation of eicosanoid synthesis in SMC and in the alterations that occur in the signaling pathways during atherosclerotic foam cell development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049666-09
Application #
6537059
Study Section
Special Emphasis Panel (ZRG4-PHRA (01))
Program Officer
Rabadan-Diehl, Cristina
Project Start
1993-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
9
Fiscal Year
2002
Total Cost
$582,432
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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