title: Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo.
abstract: Plasmalogens, 1-O-alk-1'-enyl-2-acyl-sn-glycerophospholipids, are significant constituents of cellular membranes and are essential for normal brain development. Plasmalogens, which contain a vinyl ether bond at the sn-1 position, are preferential targets for hypochlorous acid (HOCl), generated by myeloperoxidase (MPO) from H(2)O(2) and chloride ions. Because MPO is implicated in neurodegeneration, this study pursued two aims: (i) to investigate the reactivity of mouse brain plasmalogens toward HOCl in vitro and (ii) to obtain in vivo evidence for MPO-mediated brain plasmalogen modification. Liquid chromatography coupled to hybrid linear ion trap-Fourier transform-ion cyclotron resonance mass spectrometry revealed plasmalogen modification in mouse brain lipid extracts at lower HOCl concentrations as observed for diacylphospholipids, resulting in the generation of 2-chloro fatty aldehydes and lysophospholipids. Lysophosphatidylethanolamine accumulation was transient, whereas lysophosphatidylcholine species containing saturated acyl residues remained stable. In vivo, a single, systemic endotoxin injection resulted in upregulation of cerebral MPO mRNA levels to a range comparable to that observed for tumor necrosis factor-α and cyclooxygenase-2. This inflammatory response was accompanied by a significant decrease in several brain plasmalogen species and concomitant in vivo generation of 2-chlorohexadecanal. The present findings demonstrate that activation of the MPO-H(2)O(2)-chloride system under neuroinflammatory conditions results in oxidative attack of the total cerebral plasmalogen pool. As this lipid class is indispensable for normal neuronal function, HOCl-mediated plasmalogen modification is likely to compromise normal synaptic transmission.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center for Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ullen
authors.forename: Günter
authors.initials: G
authors.lastname: Fauler
authors.forename: Harald
authors.initials: H
authors.lastname: Köfeler
authors.forename: Sabine
authors.initials: S
authors.lastname: Waltl
authors.forename: Christoph
authors.initials: C
authors.lastname: Nusshold
authors.forename: Eva
authors.initials: E
authors.lastname: Bernhart
authors.forename: Helga
authors.initials: H
authors.lastname: Reicher
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Leis
authors.forename: Andrea
authors.initials: A
authors.lastname: Wintersperger
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002478:Cells, Cultured; D004983:Ethanolamines / Q000032:analysis / Q000378:metabolism; D006997:Hypochlorous Acid / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism; D010767:Phosphorylcholine / Q000032:analysis / Q000378:metabolism; D010955:Plasmalogens / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004983:Ethanolamines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010743:Phospholipids; D010955:Plasmalogens; D010767:Phosphorylcholine; D006997:Hypochlorous Acid; C005448:phosphorylethanolamine
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