Protein adducts of iso[4]levuglandin E2, a product of the isoprostane pathway, in oxidized low density lipoprotein.
Levuglandin (LG) E2, a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H2, avidly binds to proteins. That LGE2-protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE2-LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radical-induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now iso[4]LGE2-protein epitopes produced by radical-induced oxidation of arachidonic acid in the presence of protein were detected with an enzyme-linked immunosorbent assay. Iso[4]LGE2-protein epitopes are also generated during free radical-induced oxidation of LDL. All of the LGE2 isomers generated upon oxidation of LDL are efficiently sequestered by covalent adduction with LDL-based amino groups. The potent electrophilic reactivity of iso-LGs can be anticipated to have biological consequences beyond their obvious potential as markers for specific arachidonate-derived protein modifications that may be of value for the quantitative assessment of oxidative injury.
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, USA. rgs@po.cwru.edu
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Salomon
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Sha
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Brame
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Kaur
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Subbanagounder
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O'Neil
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Hoff
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Roberts
D000918:Antibody Specificity; D005609:Free Radicals; D006433:Hemocyanins / Q000276:immunology; D007769:Lactams / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D011458:Prostaglandins E / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012709:Serum Albumin / Q000276:immunology
D005609:Free Radicals; D007769:Lactams; D008077:Lipoproteins, LDL; D011453:Prostaglandins; D011458:Prostaglandins E; D011506:Proteins; D012709:Serum Albumin; C099252:oxidized low density lipoprotein; D006433:Hemocyanins; C047684:levuglandin E2; C032808:keyhole-limpet hemocyanin