Arterial prostacyclin synthesis is reduced in human atherosclerotic disease, and in animal models of atherosclerosis. However, the relationship between eicosanoids and vascular cholesterol metabolism is not clear. Experiments proposed are designed to: (i) establish an in vitro model of cholesterol accumulation by exposure of vascular smooth muscle cells to cationized LDL; (ii) determine if eicosanoid metabolism is reduced by arterial smooth muscle cells enriched in cholesterol; (iii) determine the putative mechanism(s) that cholesterol- enrichment alters eicosanoid synthetic capacity. Potential mechanisms to be studied include alterations in cellular fatty acid composition, arachidonic acid availability to cellular phospholipases, or inhibition of phospholipase A2 and C, cyclooxygenase, and/or prostacyclin synthetase. Plasma high density lipoproteins (HDL) promote net cholesterol efflux and stimulate prostacyclin and PGE2 synthesis from vascular smooth muscle cells in vitro. Prostacyclin and its hydrolytic metabolites promote net cholesterol efflux by increasing neutral and acid cholesteryl esterase (NCEH and ACEH) activities in intact smooth muscle cells. Experiments proposed are designed to (i) determine if HDL-induced eicosanoid synthesis in part mediates HDL-induced cholesterol efflux; and (ii) determine if the mechanisms of HDL-induced cholesterol efflux is due to eicosanoid-mediated alterations in ACEH, ACAT and NCEH activities. Endothelial cells (which are a major arterial source of eicosanoids) alter cholesterol metabolism in co-cultured arterial vascular smooth muscle cells. Experiments proposed are designed to (i) determine if endothelial cells modulate cholesterol content and ACEH, ACAT, and NCEH activities in cholesterol-enriched smooth muscle cells, (ii) determine if this effect is dependent upon endothelial-derived eicosanoids; and (iii) determine if HDL enhances endothelial cell-mediated cholesterol efflux from cholesterol-enriched smooth muscle cells via eicosanoid dependent mechanisms. Results from these experiments will further define the cellular mechanisms by which eicosanoids alter cholesterol metabolism in arterial smooth muscle cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039701-04
Application #
3356544
Study Section
Pathology A Study Section (PTHA)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1991-07-12
Budget End
1992-06-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Pomerantz, K B; Hajjar, D P; Levi, R et al. (1993) Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis. Biochem Biophys Res Commun 191:103-9
Kraemer, R; Pomerantz, K B; Joseph-Silverstein, J et al. (1993) Induction of basic fibroblast growth factor mRNA and protein synthesis in smooth muscle cells by cholesteryl ester enrichment and 25-hydroxycholesterol. J Biol Chem 268:8040-5
Marcus, A J; Hajjar, D P (1993) Vascular transcellular signaling. J Lipid Res 34:2017-31
Pomerantz, K B; Summers, B; Hajjar, D P (1993) Eicosanoid metabolism in cholesterol-enriched arterial smooth muscle cells. Evidence for reduced posttranscriptional processing of cyclooxygenase I and reduced cyclooxygenase II gene expression. Biochemistry 32:13624-35
Pomerantz, K B; Hajjar, D P (1991) Role of eicosanoids and the cytokine network in transmembrane signaling in vascular cells. Adv Exp Med Biol 314:159-83
Etingin, O R; Hajjar, D P; Hajjar, K A et al. (1991) Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. J Biol Chem 266:2459-65
Kim, J A; Maxwell, K; Hajjar, D P et al. (1991) Beta-VLDL increases endothelial cell plasma membrane cholesterol. J Lipid Res 32:1125-31
Etingin, O R; Silverstein, R L; Friedman, H M et al. (1990) Viral activation of the coagulation cascade: molecular interactions at the surface of infected endothelial cells. Cell 61:657-62
Hajjar, D P; Pomerantz, K B; Snow, J W (1990) Analysis of the physical state of cholesteryl esters in arterial-smooth-muscle-derived foam cells by differential scanning calorimetry. Biochem J 268:693-7
Pomerantz, K B; Hajjar, D P (1990) High-density-lipoprotein-induced cholesterol efflux from arterial smooth muscle cell derived foam cells: functional relationship of the cholesteryl ester cycle and eicosanoid biosynthesis. Biochemistry 29:1892-9

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