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: | C H, MacPhee, K E, Moores, H F, Boyd, D, Dhanak, R J, Ife, C A, Leach, D S, Leake, K J, Milliner, R A, Patterson, K E, Suckling, D G, Tew, D M, Hickey |
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| Rok vydání: | 1999 |
| Předmět: |
Aryldialkylphosphatase
Esterases Phospholipases A Lipoproteins LDL Phosphatidylcholine-Sterol O-Acyltransferase Chemotaxis Leukocyte Phospholipases A2 Sulfoxides 1-Alkyl-2-acetylglycerophosphocholine Esterase Azetidines Humans lipids (amino acids peptides and proteins) Enzyme Inhibitors Oxidation-Reduction Protein Binding Research Article |
| Zdroj: | The Biochemical journal. 338 |
| ISSN: | 0264-6021 |
| 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. 6x10(5) 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 microM, kobs/[I]=1.6x10(4) 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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