Recently we discovered a new class of ether-linked phospholipids that possesses profound antihypertensive properties (Blank et al., Biochem. Biophys. Res. Commun. 90, 1194, 1979). Independent experiments by Demopoulos et al. (J. Biol. Chem. 254, 9355, 1979) have reported the same lipid to be platelet activating factor. This biologically active phospholipid has been rigorously identified as 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (alkylacetyl-GPC). Our recent data demonstrate that alkylacetyl-GPC can be synthesized in a variety of tissues by at least two separate pathways; spleen and bone marrow were especially active. Essentially nothing is known about ether lipids that contain a short-chain acyl group at this position. Therefore, we propose to determine how alkylacetyl-GPC and its derivatives are metabolized, determined the subcellular sites for the metabolism and action of alkylacetyl-GPC, and elucidate the molecular mechanism(s) responsible for its biological properties. The possibility that alkylacetyl-GPC is a highly selective acetyl donor that modifies crucial components of the vascular system by acetylation will also be investigated. Experiments are planned to determine whether membrane binding sites exist for alkylacetyl-GPC and how this lipid transported to its site of action after oral and after intravenous administration. The possibility that alkylacetyl-GPC acts as a modifier of membrane permeability will also be examined. Although preliminary data indicate that alkylacetyl-GPC dosen't influence PGE2 synthesis from arachidonate, we plan to explore if it might affect the levels of prostacyclin and thromboxane, since a disruption in their balance could explain most of the effects elicited by alkylacetyl-GPC. The proposed investigations will be done with intact and enzymatic systems of neutrophils and platelets obtained from rabbits and with endothelial cells isolated from aortas of rabbits and rats.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027109-05
Application #
3338958
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1981-04-01
Project End
1986-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Oak Ridge Associated Universities
Department
Type
DUNS #
City
Oak Ridge
State
TN
Country
United States
Zip Code
37831
Snyder, F (1997) CDP-choline:alkylacetylglycerol cholinephosphotransferase catalyzes the final step in the de novo synthesis of platelet-activating factor. Biochim Biophys Acta 1348:111-6
Lee, T C; Ou, M C; Shinozaki, K et al. (1996) Biosynthesis of N-acetylsphingosine by platelet-activating factor: sphingosine CoA-independent transacetylase in HL-60 cels. J Biol Chem 271:209-17
Lee, T (1996) Acetylation of sphingosine by PAF-dependent transacetylase. Adv Exp Med Biol 416:113-9
Snyder, F; Fitzgerald, V; Blank, M L (1996) Biosynthesis of platelet-activating factor and enzyme inhibitors. Adv Exp Med Biol 416:5-10
Blank, M L; Smith, Z L; Fitzgerald, V et al. (1995) The CoA-independent transacylase in PAF biosynthesis: tissue distribution and molecular species selectivity. Biochim Biophys Acta 1254:295-301
Snyder, F (1995) Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes. Biochim Biophys Acta 1254:231-49
Snyder, F (1995) Platelet-activating factor: the biosynthetic and catabolic enzymes. Biochem J 305 ( Pt 3):689-705
Lee, T C; Fitzgerald, V; Chatterjee, R et al. (1994) Differentiation induced increase of platelet-activating factor acetylhydrolase in HL-60 cells. J Lipid Mediat Cell Signal 9:267-83
Blank, M L; Smith, Z L; Cress, E A et al. (1994) Molecular species of ethanolamine plasmalogens and transacylase activity in rat tissues are altered by fish oil diets. Biochim Biophys Acta 1214:295-302
Snyder, F (1994) Metabolic processing of PAF. Clin Rev Allergy 12:309-27

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