HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 10, 6428-6437, March 7, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/10/6428    most recent M709970200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Davis, B. Articles by Postle, A. D. Search for Related Content PubMed PubMed Citation Articles by Davis, B. Articles by Postle, A. D. Social Bookmarking                      What's this?

Electrospray Ionization Mass Spectrometry Identifies Substrates and Products of Lipoprotein-associated Phospholipase A₂ in Oxidized Human Low Density Lipoprotein^*

Bill Davis¹, Grielof Koster, Lisa J. Douet, Michaela Scigelova^¶, Gary Woffendin^¶, Joanna M. Ward, Alberto Smith^||, Julia Humphries^||, Kevin G. Burnand^||, Colin H. Macphee^**, and Anthony D. Postle

From the GlaxoSmithKline Clinical Unit, Cambridge, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2GG, United Kingdom, Division of Infection, Inflammation, and Repair, School of Medicine, University of Southampton SO16 6YD, United Kingdom, ^¶Thermo Electron Corp., Hemel Hempstead HP2 7GE, United Kingdom, ^||Academic Department of Surgery, Cardiovascular Division, King's College London, St. Thomas' Hospital, London SE1 7EH, United Kingdom, and ^**GlaxoSmithKline Cardiovascular Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania, 19406

There is increasing evidence that modified phospholipid products of low density lipoprotein (LDL) oxidation mediate inflammatory processes within vulnerable atherosclerotic lesions. Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is present in vulnerable plaque regions where it acts on phospholipid oxidation products to generate the pro-inflammatory lysophsopholipids and oxidized non-esterified fatty acids. This association together with identification of circulating Lp-PLA₂ levels as an independent predictor of cardiovascular disease provides a rationale for development of Lp-PLA₂ inhibitors as therapy for atherosclerosis. Here we report a systematic analysis of the effects of in vitro oxidation in the absence and presence of an Lp-PLA₂ inhibitor on the phosphatidylcholine (PC) composition of human LDL. Mass spectrometry identifies three classes of PC whose concentration is significantly enhanced during LDL oxidation. Of these, a series of molecules, represented by peaks in the m/z range 594-666 and identified as truncated PC oxidation products by accurate mass measurements using an LTQ Orbitrap mass spectrometer, are the predominant substrates for Lp-PLA₂. A second series of oxidation products, represented by peaks in the m/z range 746-830 and identified by LTQ Orbitrap analysis as non-truncated oxidized PCs, are quantitatively more abundant but are less efficient Lp-PLA₂ substrates. The major PC products of Lp-PLA₂, saturated and mono-unsaturated lyso-PC, constitute the third class. Mass spectrometric analysis confirms the presence of many of these PCs within human atherosclerotic lesions, suggesting that they could potentially be used as in vivo markers of atherosclerotic disease progression and response to Lp-PLA₂ inhibitor therapy.

Received for publication, December 6, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2.

¹ To whom correspondence should be addressed. Tel.: 44-1223-296126; E-mail: Bill.G.Davis{at}GSK.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Chen, X. Chen, R. G. Salomon, and T. M. McIntyre Platelet Activation by Low Concentrations of Intact Oxidized LDL Particles Involves the PAF Receptor Arterioscler. Thromb. Vasc. Biol., March 1, 2009; 29(3): 363 - 371. [Abstract] [Full Text] [PDF]

				U. Samanta and B. J. Bahnson Crystal Structure of Human Plasma Platelet-activating Factor Acetylhydrolase: STRUCTURAL IMPLICATION TO LIPOPROTEIN BINDING AND CATALYSIS J. Biol. Chem., November 14, 2008; 283(46): 31617 - 31624. [Abstract] [Full Text] [PDF]

				P. W. Serruys, H. M. Garcia-Garcia, P. Buszman, P. Erne, S. Verheye, M. Aschermann, H. Duckers, O. Bleie, D. Dudek, H. E. Botker, et al. Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque Circulation, September 9, 2008; 118(11): 1172 - 1182. [Abstract] [Full Text] [PDF]