Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor
| Autor: | Helen F. Boyd, Deirdre M. B. Hickey, Kitty Moores, Kevin J. Milliner, Colin H. Macphee, Dash Dhanak, Keith E. Suckling, Leach Colin Andrew, Rebecca A. Patterson, Robert John Ife, David S. Leake, David G. Tew |
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| Rok vydání: | 1999 |
| Předmět: |
chemistry.chemical_classification
biology Lipoprotein-associated phospholipase A2 Fatty acid Cell Biology 1-Alkyl-2-acetylglycerophosphocholine Esterase Biochemistry chemistry.chemical_compound Phospholipase A2 Lysophosphatidylcholine chemistry Low-density lipoprotein biology.protein lipids (amino acids peptides and proteins) Chemoattractant activity Molecular Biology Lipoprotein |
| Zdroj: | Biochemical Journal. 338:479-487 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj3380479 |
| Popis: | A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki = 40±3 nM, kobs/[I] = 6.6×105 M-1·s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0±0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki = 6.3±0.5 µM, kobs/[I] = 1.6×104 M-1·s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine. |
| Databáze: | OpenAIRE |
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