Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo.
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.
Ullen
Andreas
A
Institute of Molecular Biology and Biochemistry, Center for Molecular Medicine, Medical University of Graz, Graz, Austria.
Fauler
Günter
G
Köfeler
Harald
H
Waltl
Sabine
S
Nusshold
Christoph
C
Bernhart
Eva
E
Reicher
Helga
H
Leis
Hans-Jörg
HJ
Wintersperger
Andrea
A
Malle
Ernst
E
Sattler
Wolfgang
W
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
D004983:Ethanolamines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010743:Phospholipids; D010955:Plasmalogens; D010767:Phosphorylcholine; D006997:Hypochlorous Acid; C005448:phosphorylethanolamine
J Biol Chem. 2001 Jun 29;276(26):23733-41
11301330
Biochim Biophys Acta. 2006 Dec;1763(12):1511-26
17027098
Neurotoxicology. 2008 Sep;29(5):864-70
18471886
Pharmacol Ther. 2007 Sep;115(3):400-9
17658610
Mol Neurobiol. 2010 Jun;41(2-3):267-73
20049656
J Neurosci. 2005 Jul 13;25(28):6594-600
16014720
Lab Invest. 2002 Jan;82(1):5-14
11796821
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18584-9
19011099
Chem Phys Lipids. 2004 Aug;131(1):93-105
15210368
Biochemistry. 1990 May 22;29(20):4992-6
2364071
Nucleic Acids Res. 2002 May 1;30(9):e36
11972351
Brain. 2007 Nov;130(Pt 11):2800-15
17956913
Blood Cells Mol Dis. 2008 Sep-Oct;41(2):196-9
18501647
Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2955-64
15681699
J Leukoc Biol. 2005 May;77(5):598-625
15689384
J Neurochem. 2001 May;77(4):1168-80
11359882
J Lipid Res. 1965 Oct;6(4):537-44
5865382
Brain. 2008 Apr;131(Pt 4):1123-33
18234693
Eur J Biochem. 2000 Jul;267(14):4495-503
10880973
J Lipid Res. 2007 Jun;48(6):1316-24
17395985
Biochim Biophys Acta. 2006 Dec;1763(12):1733-48
17055079
Free Radic Biol Med. 2003 Mar 1;34(5):553-62
12614844
Glia. 2007 Apr 1;55(5):453-62
17203472
Hum Mol Genet. 2003 Aug 1;12(15):1881-95
12874108
Chem Phys Lipids. 2009 Sep;161(1):44-50
19577554
Biochemistry. 1995 Sep 26;34(38):12193-203
7547960
Hum Mutat. 2005 Jul;26(1):1-10
15931689
Biochemistry. 2008 Aug 5;47(31):8237-45
18605737
PLoS One. 2007 Dec 26;2(12):e1368
18159251
J Biol Chem. 1957 May;226(1):497-509
13428781
Hum Mol Genet. 2001 Jan 15;10(2):127-36
11152660
Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2302-6
15514213
J Chromatogr A. 2010 Jun 18;1217(25):4229-39
20452604
Anal Biochem. 2008 May 1;376(1):157-9
18295587
J Neurochem. 2004 Aug;90(3):724-33
15255951
Brain Res. 1995 Nov 6;698(1-2):223-6
8581486
Chem Phys Lipids. 2006 Oct;144(1):34-44
16859663
Exp Neurol. 1999 Jan;155(1):31-41
9918702
J Neurochem. 2006 Jun;97(6):1634-58
16805774
Biochemistry. 2005 May 17;44(19):7378-87
15882077
J Clin Invest. 1996 Mar 15;97(6):1535-44
8617887
Brain Res. 2000 Jun 9;867(1-2):9-18
10837793
J Biol Chem. 2006 Jun 23;281(25):16849-16860
16611638
Nat Med. 2010 Apr;16(4):470-4
20305660
J Lipid Res. 2007 Nov;48(11):2485-98
17664527
Blood. 1975 Dec;46(6):913-9
173439
J Biol Chem. 2009 Jan 30;284(5):3158-3169
19059911
Hum Mol Genet. 2009 Jun 1;18(11):1897-908
19270340
J Lipid Res. 2010 May;51(5):1085-92
20019386
Biochemistry. 1994 May 17;33(19):5805-12
8180209
J Neurochem. 2007 Nov;103 Suppl 1:171-9
17986152
J Neurochem. 2007 May;101(3):577-99
17257165
J Biol Chem. 2003 Sep 19;278(38):36365-72
12869568
Biochemistry. 2006 Nov 28;45(47):14201-11
17115715
Cell Signal. 2007 Feb;19(2):219-28
16959471
Brain. 2009 Feb;132(Pt 2):482-92
19022859
J Biol Chem. 2002 Feb 8;277(6):3842-9
11724792
Free Radic Biol Med. 2010 Jun 15;48(12):1588-600
20226853
Brain Res. 2004 Oct 1;1022(1-2):1-11
15353207
Brain Pathol. 2008 Jan;18(1):86-95
18042261
J Biochem. 2000 Jun;127(6):971-6
10833264
Glia. 2003 Jan;41(1):3-14
12465041
Chem Phys Lipids. 2006 Feb;139(2):157-70
16417904
Cell Tissue Res. 2009 Aug;337(2):281-99
19495798
J Neuroimmunol. 1997 Sep;78(1-2):97-107
9307233
Glia. 2007 Nov 15;55(15):1577-88
17823975
Circulation. 2003 Dec 23;108(25):3128-33
14638540
Brain Behav Immun. 2010 Jan;24(1):102-9
19735725