Fluorescent adducts formed by reaction of oxidized unsaturated fatty acids with amines increase macrophage viability |
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Authors: | Riazy Maziar Lougheed Marilee Adomat Hans H Guns Emma S Tomlinson Eigendorf Guenter K Duronio Vincent Steinbrecher Urs P |
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Affiliation: | Department of Medicine, University of British Columbia, and Vancouver Coastal Health Research Institute, Vancouver, BC, Canada. mriazy@interchange.ubc.ca |
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Abstract: | Macrophages are prominent components of human atherosclerotic lesions and they are believed to accelerate the progression and/or complications of both early and advanced atherosclerotic lesions. We and others have shown that oxidized low-density lipoprotein (oxLDL) induces growth and inhibits apoptosis in murine bone marrow-derived macrophages. In this study, we sought to characterize the oxidative modification of LDL that is responsible for this prosurvival effect. We found that both the modified lipid and the modified protein components of oxLDL can increase the viability of macrophages. The key modification appeared to involve derivatization of amino groups in apoB or in phosphatidylethanolamine by lipid peroxidation products. These reactive oxidation products were primarily unfragmented hydroperoxide- or endoperoxide-containing oxidation products of linoleic acid or arachidonic acid. LC-MS/MS studies showed that some of the arachidonic acid-derived lysine adducts were isolevuglandins that contain lactam and hydroxylactam rings. MS/MS analysis of linoleic acid autoxidation adducts was consistent with 5- or 6-membered nitrogen-containing heterocycles derived from unfragmented oxidation products. The amine modification by oxidation products generated a fluorescence pattern with an excitation maximum at 350nm and emission maximum at 430nm. This is very similar to the fluorescence spectrum of copper-oxidized LDL. |
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Keywords: | HHE, 4-hydroxyhexenal HNE, 4-hydroxynonenal AA, arachidonic acid AOP-LDL, arachidonate oxidation product-modified LDL apo, apolipoprotein BHT, butylated hydroxytoluene ESI, electrospray ionization FBS, fetal bovine serum isoLG, isolevuglandin LA, linoleic acid LDL, low-density lipoprotein LME, smallcaps" >l-lysine methyl ester LOP-LDL, linoleate oxidation product-modified LDL LPC, lysophosphatidylcholine MPM, mouse peritoneal macrophage MS/MS, tandem mass spectrometry OP, oxidation product OP-LDL, oxidation product-modified LDL oxLDL, oxidized LDL PC, phosphatidylcholine PE, phosphatidylethanolamine p-HA, p-hydroxyphenylacetaldehyde PI3K, phosphatidylinositol 3-kinase PKB, protein kinase B TPP, triphenylphosphine XTT, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide |
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