Inhibition of lipoprotein‐associated phospholipase A2 diminishes the death‐inducing effects of oxidised LDL on human monocyte‐macrophages

FEBS Letters

Arends, Mark J.³  Leake, David S.¹  Macphee, Colin H.⁴  Challis, Iain R.³  Dennis, Ian F.³  Carpenter, Keri L.H.³  Osborn, David P.²  Mitchinson, Malcolm J.³ 

[1] Cell and Molecular Biology Research Division, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, P.O. Box 228, Reading RG6 6AJ, UK;University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK;Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK;Department of Vascular Biology, Glaxo SmithKline Pharmaceuticals, New Frontiers Science Park North, Third Avenue, The Pinnacles, Harlow CM19 5AW, UK

关键词: Toxicity;    Oxidized low-density lipoprotein;    Lipoprotein-associated phospholipase A2;    Lysophosphatidylcholine;    Oxidized phospholipid;    Monocyte-macrophage (human);    CECA;    cholesterol ester-derived core aldehyde;    DCM;    dichloromethane;    DFP;    diisopropyl fluorophosphate;    DMS;    dimethylsulphide;    DMSO;    dimethylsulphoxide;    DNPH;    2;    4-dinitrophenylhydrazone;    ELISA;    enzyme-linked immunosorbent assay;    GC;    gas chromatography;    HDL;    high-density lipoprotein;    HMM;    human monocyte-macrophage;    HNE;    4-hydroxynon-2-enal;    HPLC;    high pressure liquid chromatography;    7β-HC;    7β-hydroxycholesterol;    IN-oxLDL;    inhibitor-pretreated oxidised low-density lipoprotein;    IPA;    isopropanol;    LDH;    lactate dehydrogenase;    LDL;    low-density lipoprotein;    Lp-PLA2;    lipoprotein-associated phospholipase A2;    lyso-PC;    lysophosphatidylcholine;    M/DAG;    mono- and diacylglycerol;    oxLDL;    oxidised low-density lipoprotein;    oxNEFA;    oxidised non-esterified fatty acid;    PAF;    platelet-activating factor;    PAF-AH;    platelet-activating factor acetylhydrolase;    PC;    phosphatidylcholine;    PC-9-oxo;    1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine;    PCCA;    PC-derived core aldehyde;    REM;    relative electrophoretic mobility;    SMC;    smooth muscle cell;    TBARS;    thiobarbituric acid-reactive substances;    TLC;    thin layer chromatography;   

DOI  :  10.1016/S0014-5793(01)02840-X

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The death of macrophages contributes to atheroma formation. Oxidation renders low-density lipoprotein (LDL) cytotoxic to human monocyte-macrophages. Lipoprotein-associated phospholipase A₂ (Lp-PLA₂), also termed platelet-activating factor acetylhydrolase, hydrolyses oxidised phospholipids. Inhibition of Lp-PLA₂ by diisopropyl fluorophosphate or Pefabloc (broad-spectrum serine esterase/protease inhibitors), or SB222657 (a specific inhibitor of Lp-PLA₂) did not prevent LDL oxidation, but diminished the ensuing toxicity and apoptosis induction when the LDL was oxidised, and inhibited the rise in lysophosphatidylcholine levels that occurred in the inhibitors’ absence. Hydrolysis products of oxidised phospholipids thus account for over a third of the cytotoxic and apoptosis-inducing effects of oxidised LDL on macrophages.

【 授权许可】

Unknown