Myeloperoxidase-derived Reactive Chlorinating Species from Human Monocytes Target Plasmalogens in Low Density Lipoprotein

A role for myeloperoxidase (MPO) in atherosclerosis has received considerable attention recently. To identify potential chlorinated lipid products in human low density lipoprotein (LDL), studies were designed to demonstrate that MPO-derived reactive chlorinating species (RCS) target the plasmalogen pool of LDL isolated from peripheral human blood in vitro. The vinyl ether bond of LDL plasmalogens was targeted by MPO-derived RCS, resulting in the release of the 16- and 18-carbon-containing α-chloro fatty aldehydes, 2-chlorohexadecanal and 2-chlorooctadecanal, respectively, from the plasmalogen glycerol backbone. Targeting of the LDL plasmalogen vinyl ether bond was dependent on the presence of MPO-derived RCS. Electrospray ionization mass spectrometric analysis of MPO-treated LDL demonstrated that a novel population of unsaturated lysophosphatidylcholine molecular species was produced by a phospholipase A2-independent mechanism. Unsaturated lysophosphatidylcholine molecular species elicited cyclic AMP response element binding protein phosphorylation in RAW 264.7 cells. Additionally, MPO-mediated targeting of both monocyte and LDL plasmalogen pools was demonstrated in phorbol myristate acetate-stimulated human monocytes, resulting in the production of both 2-chlorohexadecanal and 2-chlorooctadecanal. In contrast, α-chloro fatty aldehydes were not produced in phorbol myristate acetate-stimulated mouse monocytes. Collectively, the present studies demonstrate a novel MPO-specific mechanism that mediates the production of a novel group of unsaturated lysophosphatidylcholine molecular species and chlorinated aldehydes from both LDL and monocyte plasmalogen pools that may have important effects during inflammatory reactions mediated by monocytes, most notably atherosclerosis. A role for myeloperoxidase (MPO) in atherosclerosis has received considerable attention recently. To identify potential chlorinated lipid products in human low density lipoprotein (LDL), studies were designed to demonstrate that MPO-derived reactive chlorinating species (RCS) target the plasmalogen pool of LDL isolated from peripheral human blood in vitro. The vinyl ether bond of LDL plasmalogens was targeted by MPO-derived RCS, resulting in the release of the 16- and 18-carbon-containing α-chloro fatty aldehydes, 2-chlorohexadecanal and 2-chlorooctadecanal, respectively, from the plasmalogen glycerol backbone. Targeting of the LDL plasmalogen vinyl ether bond was dependent on the presence of MPO-derived RCS. Electrospray ionization mass spectrometric analysis of MPO-treated LDL demonstrated that a novel population of unsaturated lysophosphatidylcholine molecular species was produced by a phospholipase A2-independent mechanism. Unsaturated lysophosphatidylcholine molecular species elicited cyclic AMP response element binding protein phosphorylation in RAW 264.7 cells. Additionally, MPO-mediated targeting of both monocyte and LDL plasmalogen pools was demonstrated in phorbol myristate acetate-stimulated human monocytes, resulting in the production of both 2-chlorohexadecanal and 2-chlorooctadecanal. In contrast, α-chloro fatty aldehydes were not produced in phorbol myristate acetate-stimulated mouse monocytes. Collectively, the present studies demonstrate a novel MPO-specific mechanism that mediates the production of a novel group of unsaturated lysophosphatidylcholine molecular species and chlorinated aldehydes from both LDL and monocyte plasmalogen pools that may have important effects during inflammatory reactions mediated by monocytes, most notably atherosclerosis. Myeloperoxidase (MPO), 1The abbreviations used are: MPO, myeloperoxidase; HOCl, hypochlorous acid; RCS, reactive chlorinating species; LDL, low density lipoprotein; LPC, lysophosphatidylcholine; 2-Cl-[d 4]-HDA, 2-chloro-[7,7,8,8-d 4]-hexadecanal; PFB, pentafluorobenzyl; CREB, cyclic AMP response element binding protein; pCREB, phospho-CREB; ATZ, 3-aminotriazole; GC-MS, gas chromatography-mass spectrometry; ESI-MS, electrospray ionization mass spectrometry; NICI, negative ion chemical ionization; 2-ClHDA, 2-chlorohexadecanal; SIM, selected ion monitoring; 2-ClODA, 2-chlorooctadecanal; DMEM, Dulbecco's Modified Eagle medium; HBSS, Hanks' balanced salt solution; PMA, phorbol myristate acetate.1The abbreviations used are: MPO, myeloperoxidase; HOCl, hypochlorous acid; RCS, reactive chlorinating species; LDL, low density lipoprotein; LPC, lysophosphatidylcholine; 2-Cl-[d 4]-HDA, 2-chloro-[7,7,8,8-d 4]-hexadecanal; PFB, pentafluorobenzyl; CREB, cyclic AMP response element binding protein; pCREB, phospho-CREB; ATZ, 3-aminotriazole; GC-MS, gas chromatography-mass spectrometry; ESI-MS, electrospray ionization mass spectrometry; NICI, negative ion chemical ionization; 2-ClHDA, 2-chlorohexadecanal; SIM, selected ion monitoring; 2-ClODA, 2-chlorooctadecanal; DMEM, Dulbecco's Modified Eagle medium; HBSS, Hanks' balanced salt solution; PMA, phorbol myristate acetate. a bactericidal enzyme secreted by activated phagocytes, specifically catalyzes the production of hypochlorous acid (HOCl) from chloride and hydrogen peroxide (1Albrich J.M. McCarthy C.A. Hurst J.K. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 210-214Crossref PubMed Scopus (380) Google Scholar, 2Harrison J.E. Schultz J. J. Biol. Chem. 1976; 251: 1371-1374Abstract Full Text PDF PubMed Google Scholar). HOCl, in equilibrium with both its conjugate anion –OCl and molecular Cl2 collectively compose the major reactive chlorinating species (RCS) produced by phagocytes. These RCS mediate a number of potentially deleterious reactions, which include the chlorination of unsaturated aliphatic groups (3Winterbourn C.C. van den Berg J.J. Roitman E. Kuypers F.A. Arch. Biochem. Biophys. 1992; 296: 547-555Crossref PubMed Scopus (226) Google Scholar) and tyrosine (4Hazen S.L. Heinecke J.W. J. Clin. Invest. 1997; 99: 2075-2081Crossref PubMed Scopus (744) Google Scholar), oxidative bleaching of heme iron and sulfur protein centers (1Albrich J.M. McCarthy C.A. Hurst J.K. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 210-214Crossref PubMed Scopus (380) Google Scholar, 5Weiss S.J. Klein R. Slivka A. Wei M. J. Clin. Invest. 1982; 70: 598-607Crossref PubMed Scopus (665) Google Scholar, 6Thomas E.L. Jefferson M.M. Grisham M.B. Biochemistry. 1982; 21: 6299-6308Crossref PubMed Scopus (108) Google Scholar, 7Heinecke J.W. Li W. Mueller D.M. Bohrer A. Turk J. Biochemistry. 1994; 33: 10127-10136Crossref PubMed Scopus (138) Google Scholar), as well as the generation of equally reactive and potentially damaging chloramines with primary amine groups (8Lampert M.B. Weiss S.J. Blood. 1983; 62: 645-651Crossref PubMed Google Scholar). Atherosclerosis is an inflammatory arterial pathology occurring most significantly in coronary and carotid arteries. Atherosclerosis is characterized by the development of immature fatty streaks that progress into mature plaques, attributable in part to the accumulation of necrosing oxidized low density lipoprotein (LDL)-laden macrophages termed foam cells in the arterial tunica intima. Although atherosclerotic lesions in wild-type mice do not contain MPO-derived products and MPO-knock-out mice have larger atherosclerotic lesions in comparison with wild-type mice (9Brennan M.L. Anderson M.M. Shih D.M. Qu X.D. Wang X. Mehta A.C. Lim L.L. Shi W. Hazen S.L. Jacob J.S. Crowley J.R. Heinecke J.W. Lusis A.J. J. Clin. Invest. 2001; 107: 419-430Crossref PubMed Scopus (275) Google Scholar), multiple studies have implicated MPO with human atherosclerotic pathophysiology. Active MPO has been isolated from human atherosclerotic tissue (10Daugherty A. Dunn J.L. Rateri D.L. Heinecke J.W. J. Clin. Invest. 1994; 94: 437-444Crossref PubMed Scopus (1103) Google Scholar), and the MPO-specific product 3-chlorotyrosine (4Hazen S.L. Heinecke J.W. J. Clin. Invest. 1997; 99: 2075-2081Crossref PubMed Scopus (744) Google Scholar) as well as HOCl-modified proteins (11Malle E. Waeg G. Schreiber R. Grone E.F. Sattler W. Grone H.J. Eur. J. Biochem. 2000; 267: 4495-4503Crossref PubMed Scopus (216) Google Scholar) has been detected at elevated levels in atherosclerotic lesions as compared with normal vascular tissue. Additionally, elevated blood and leukocyte MPO levels have been shown to significantly correlate with the presence of coronary artery atherosclerosis in patients (12Zhang R. Brennan M.L. Fu X. Aviles R.J. Pearce G.L. Penn M.S. Topol E.J. Sprecher D.L. Hazen S.L. JAMA. 2001; 286: 2136-2142Crossref PubMed Scopus (753) Google Scholar). Lastly, HOCl has been shown to activate matrilysin (matrix metalloproteinase-7) in vitro, and MPO colocalizes with this matrix metalloproteinase in tissue sections from vulnerable plaques, suggesting a role for MPO in the process of plaque rupture as well (13Fu X. Kassim S.Y. Parks W.C. Heinecke J.W. J. Biol. Chem. 2001; 276: 41279-41287Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar). Plasmalogens are a glycerophospholipid species enriched in the plasma membranes of many cells present in the mammalian cardiovascular system and are characterized by the presence of a vinyl ether bond-linked aliphatic chain at the sn-1 position (14Hazen S.L. Hall C.R. Ford D.A. Gross R.W. J. Clin. Invest. 1993; 91: 2513-2522Crossref PubMed Scopus (66) Google Scholar, 15Ford D.A. Gross R.W. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3479-3483Crossref PubMed Scopus (107) Google Scholar, 16Gross R.W. Biochemistry. 1984; 23: 158-165Crossref PubMed Scopus (233) Google Scholar, 17Han X. Gross R.W. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10635-10639Crossref PubMed Scopus (368) Google Scholar). The physiological importance of plasmalogens likely includes roles as storage depots of esterified arachidonic acid (15Ford D.A. Gross R.W. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3479-3483Crossref PubMed Scopus (107) Google Scholar, 16Gross R.W. Biochemistry. 1984; 23: 158-165Crossref PubMed Scopus (233) Google Scholar, 17Han X. Gross R.W. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10635-10639Crossref PubMed Scopus (368) Google Scholar) as well as the solvation of transmembrane proteins such as the sodium-calcium exchanger (18Ford D.A. Hale C.C. FEBS Lett. 1996; 394: 99-102Crossref PubMed Scopus (53) Google Scholar, 19Pak J.H. Bork V.P. Norberg R.E. Creer M.H. Wolf R.A. Gross R.W. Biochemistry. 1987; 26: 4824-4830Crossref PubMed Scopus (46) Google Scholar, 20Zeng Y. Han X. Gross R.W. Biochemistry. 1998; 37: 2346-2355Crossref PubMed Scopus (19) Google Scholar). Because plasmalogens have been identified in human lipoproteins (21Engelmann B. Brautigam C. Thiery J. Biochem. Biophys. Res. Commun. 1994; 204: 1235-1242Crossref PubMed Scopus (110) Google Scholar) and because LDL attack by MPO-derived RCS produced from macrophages has been considered to be at least one mechanism leading to LDL modification and subsequent foam cell development (22Podrez E.A. Schmitt D. Hoff H.F. Hazen S.L. J. Clin. Invest. 1999; 103: 1547-1560Crossref PubMed Scopus (416) Google Scholar), the present studies were performed to determine the susceptibility of human LDL plasmalogen pools to RCS attack. The present findings now demonstrate that human LDL plasmalogens are attacked by MPO-derived RCS, resulting in the production of α-chloro fatty aldehydes as well as unsaturated lysophosphatidylcholine (LPC) molecular species. Furthermore, activated human monocytes produce RCS that attack both monocyte and LDL plasmalogen pools to produce α-chloro fatty aldehydes as well. 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Because LDL lipid pools plasmalogens with unsaturated aliphatic groups at the be that the targeting of the sn-1 vinyl ether bond of LDL by RCS unsaturated molecular species. lipid from LDL with and RCS were by in the ion of LDL with MPO in the generation of unsaturated molecular species LPC, LPC, and which are present at significantly levels compared with in the of unsaturated molecular species were by RCS attack of LDL the targeting of the sn-1 aliphatic chain of the Collectively, this for the a novel mechanism on MPO-derived RCS targeting of plasmalogens that a population of novel unsaturated species a phospholipase A2-independent mechanism. studies were performed to determine the potential of unsaturated molecular species produced by RCS attack of LDL RAW 264.7 cells in were with LPC, and phosphorylation of the was shown in demonstrate that both and elicited in phosphorylation in to phosphorylation to as of both molecular species were to be that these of unsaturated molecular species are the in this In contrast, not phosphorylation not studies were performed to determine activated monocytes produce RCS that target LDL that the of to vinyl ether aliphatic in LDL plasmalogen pools was that in the human monocyte plasmalogen pool not in that of human monocytes the production of both and that is with cells. Additionally, α-chloro fatty levels in human monocytes in the presence of In both the presence and of LDL, human α-chloro fatty aldehydes produced in response to were of the of compared with The presence of the production of α-chloro fatty production Furthermore, analysis of the that α-chloro fatty aldehydes were present human monocytes were in the presence of LDL the in the of in the in comparison to the with the human monocytes that LDL plasmalogen pools were the of RCS from monocytes. studies were performed mouse monocytes, which contain of the plasmalogen that in human monocytes. In to the with human monocytes, of mouse monocytes with not in α-chloro fatty production that was in these studies with mouse monocytes, α-chloro fatty in the both the presence and of human LDL in the was not during mouse monocyte with Although MPO has been implicated as a of atherosclerosis (4Hazen S.L. Heinecke J.W. J. Clin. Invest. 1997; 99: 2075-2081Crossref PubMed Scopus (744) Google Scholar, A. Dunn J.L. Rateri D.L. Heinecke J.W. J. Clin. Invest. 1994; 94: 437-444Crossref PubMed Scopus (1103) Google Scholar, R. Brennan M.L. Fu X. Aviles R.J. Pearce G.L. Penn M.S. Topol E.J. Sprecher D.L. Hazen S.L. JAMA. 2001; 286: 2136-2142Crossref PubMed Scopus (753) Google Scholar, X. Kassim S.Y. Parks W.C. Heinecke J.W. J. Biol. Chem. 2001; 276: 41279-41287Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar), the mechanism by which MPO has not been Furthermore, chlorinated lipid species produced from RCS attack of and lipoprotein not been In the studies MPO-derived RCS have been shown to target LDL plasmalogen pools in both in and human monocyte cell the vinyl ether bond of LDL plasmalogens are resulting in the release of the α-chloro fatty aldehydes, and 2-ClODA, from the glycerol of RCS attack of LDL plasmalogen pools produced novel unsaturated molecular species that may to atherosclerotic development of be that multiple studies have a role for MPO in human atherosclerosis (4Hazen S.L. Heinecke J.W. J. Clin. Invest. 1997; 99: 2075-2081Crossref PubMed Scopus (744) Google Scholar, A. Dunn J.L. Rateri D.L. Heinecke J.W. J. Clin. Invest. 1994; 94: 437-444Crossref PubMed Scopus (1103) Google Scholar, E. Waeg G. Schreiber R. Grone E.F. Sattler W. Grone H.J. Eur. J. Biochem. 2000; 267: 4495-4503Crossref PubMed Scopus (216) Google Scholar, R. Brennan M.L. Fu X. Aviles R.J. Pearce G.L. Penn M.S. Topol E.J. Sprecher D.L. Hazen S.L. JAMA. 2001; 286: 2136-2142Crossref PubMed Scopus (753) Google Scholar, X. Kassim S.Y. Parks W.C. Heinecke J.W. J. Biol. Chem. 2001; 276: 41279-41287Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar), MPO is not present in atherosclerotic lesions (9Brennan M.L. Anderson M.M. Shih D.M. Qu X.D. Wang X. Mehta A.C. Lim L.L. Shi W. Hazen S.L. Jacob J.S. Crowley J.R. Heinecke J.W. Lusis A.J. J. Clin. Invest. 2001; 107: 419-430Crossref PubMed Scopus (275) Google Scholar). The present findings this important and of human monocytes to the production of the plasmalogen α-chloro fatty aldehydes, these products are not in activated mouse monocytes. likely is by the of MPO in human monocytes compared with mouse monocytes (9Brennan M.L. Anderson M.M. Shih D.M. Qu X.D. Wang X. Mehta A.C. Lim L.L. Shi W. Hazen S.L. 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The production of unsaturated molecular species by RCS targeting of plasmalogens a phospholipase A2-independent mechanism for be that in comparison to by phospholipase the production of unsaturated by RCS targeting of plasmalogens not be to the of such molecular species and have been shown to activate cyclic protein leading to phosphorylation Ford D.A. J. 2001; PubMed Google Scholar, Ford D.A. FEBS Lett. 1997; PubMed Scopus Google Scholar). Furthermore, has that to roles in atherosclerosis contain cyclic AMP response in most notably Y. S. S. Y. Y. M. Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar). Plasmalogens have been as storage depots for esterified arachidonic acid (15Ford D.A. Gross R.W. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3479-3483Crossref PubMed Scopus (107) Google Scholar, 16Gross R.W. Biochemistry. 1984; 23: 158-165Crossref PubMed Scopus (233) Google Scholar, 17Han X. Gross R.W. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10635-10639Crossref PubMed Scopus (368) Google Scholar) and as transmembrane proteins (18Ford D.A. Hale C.C. FEBS Lett. 1996; 394: 99-102Crossref PubMed Scopus (53) Google Scholar, 19Pak J.H. Bork V.P. Norberg R.E. Creer M.H. Wolf R.A. Gross R.W. Biochemistry. 1987; 26: 4824-4830Crossref PubMed Scopus (46) Google Scholar). studies have that plasmalogens may be by as during lipoprotein because the vinyl ether bond as a for reactions mediated by reactive species (21Engelmann B. Brautigam C. Thiery J. Biochem. Biophys. Res. Commun. 1994; 204: 1235-1242Crossref PubMed Scopus (110) Google Scholar). In contrast, the attack of the vinyl ether bond by RCS potentially important α-chloro fatty aldehydes and unsaturated molecular that may as important signaling in inflammatory