Key points are not available for this paper at this time.
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. 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. The identification of Lp-PLA2 2The abbreviations used are:Lp-PLA2lipoprotein-associated phospholipase A2LDLlow density lipoproteinLPClysophosphatidylcholinePCphosphatidylcholineBHTbutylated hydroxytoluenenLDLnative LDLoxLDLoxidized LDLox + iLDLLDL oxidized in the presence of SB222657HPLChigh performance liquid chromatographyMSmass spectroscopy. as a strong independent predictor of cardiovascular disease (1Packard C.J. O'Reilly D.S. Caslake M.J. McMahon A.D. Ford I. Cooney J. Macphee C.H. Suckling K.E. Krishna M. Wilkinson F.E. Rumley A. Lowe G.D. N. Engl. J. Med. 2000; 343: 1148-1155Crossref PubMed Scopus (769) Google Scholar, 2Caslake M.J. Packard C.J. Suckling K.E. Holmes S.D. Chamberlain P. Macphee C.H. Atherosclerosis. 2000; 150: 413-419Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 3Koenig W. Khuseyinova N. Lowel H. Trischler G. Meisinger C. Circulation. 2004; 110: 1903-1908Crossref PubMed Scopus (283) Google Scholar, 4Oei H.H. van d.M.I. Hofman A. 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Chem. Full Text PDF PubMed Google Scholar, D. McIntyre T.M. Prescott S.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), and products of LDL oxidation may be to The products of the and oxidized non-esterified fatty have both been to mediate potentially processes in vitro H. K. H. N. T. Atherosclerosis. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. N. S. M. H. H. E. H. M. N. T. 1999; PubMed Scopus Google Scholar, M. K. K. M. H. T. J. Circulation. 1998; PubMed Scopus Google Scholar, C.H. K.E. D. D.S. Suckling K.E. J. 1999; PubMed Scopus Google Scholar, H. T. S. K. T. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Lp-PLA2 during in vitro LDL oxidation has been to of the oxidized LDL in the of C.H. K.E. D. D.S. Suckling K.E. J. 1999; PubMed Scopus Google Scholar) and Macphee C.H. D.S. M.J. M.J. 2001; PubMed Scopus Google Scholar). with increasing evidence that the enzyme is present within atherosclerotic and in vulnerable regions E. Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar, M. A. K.G. P. S. Suckling K.E. C.H. Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar) have a rationale to development of Lp-PLA2 inhibitors as possible Macphee C.H. 2001; PubMed Scopus Google Scholar, K.E. Macphee C.H. Opin. 2002; 6: PubMed Scopus Google Scholar, C.H. J. A. Curr. Opin. Pharmacol. 6: PubMed Scopus Google Scholar). the of Lp-PLA2 the have been in vitro in Here we have used mass spectrometry to the in phosphatidylcholine (PC) species during in vitro oxidation of human LDL and the modifications by the presence of an Lp-PLA2 C.H. K.E. D. D.S. Suckling K.E. J. 1999; PubMed Scopus Google Scholar) during oxidation. classes of PC products of LDL oxidation on the of of by Lp-PLA2 and that saturated and are the predominant PC products of the Mass spectrometric analysis of lipid human confirms the presence of many of these in human atherosclerotic lesions. phospholipase A2 low density lipoprotein phosphatidylcholine LDL oxidized LDL LDL oxidized in the presence of performance liquid mass spectroscopy. and of human with and by in V.N. PubMed Scopus Google Scholar). a in to by the of of and for The low density and the and of The density to by the of of and to by the of and the and in a of by a and for a of LDL and in Lp-PLA2 inhibitor and and for LDL and the of for oxidized and for and to the oxidized LDL lipid of LDL of LDL using the of and J. PubMed Scopus Google Scholar). A of PC and in of to as and to in a and to a A by the of a of and by and in an using The a a of and for a of a range of we that of PC and that of the of the and a of PC and of with The and of plaque using a of to of and of together with PC and with an for with in an of of and of to a and with to by for The and as Mass lipid in and by a of the of a mass of oxidized and species a of m/z A.N. A.D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of m/z used to PC that the of polyunsaturated PC species with species M. P. P. J. Res. 2001; Full Text Full Text PDF PubMed Google Scholar), we possible The response of to of and more of that the analysis of species within the concentration range of in of fatty acyl of PC species by of PC species generate and species by of a the for Mass spectrometric and using to for the and the formation of the with increasing mass A.N. A.D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of PC by Mass mass on a mass used in both and The using an and in a with of of and of The and for analysis to and the the the to for and to a a The with a the for the mass The to the of the The with the of m/z to the of The mass for of the species of oxidized PCs identified in PC for LDL to PC concentration a in the LDL The the S.D. of LDL of PC in LDL oxidized LDL and LDL oxidized in the presence of + by using analysis of LDL with the absence of and for and to the PC species composition of LDL. the for to have to on the that of lipid for oxidation mass of LDL PC with and to are in A and as of the m/z in are to the for the that oxidation with in the absence of and of LDL PC species m/z and and of m/z and the and of the PC and by LTQ Orbitrap mass together with and species identified the fatty acyl by of the in the of species m/z and and of a series of m/z to in of the oxidation products are of PC species oxidation are in and as the of LDL by of and lipid class. PC the of the in concentration with the of fatty acyl of PC species of and fatty and in concentration of the major mono-unsaturated The concentration of PC oxidation in the suggesting that a of the PC the oxidation to a where it a species that in the range of and LDL phosphatidylcholine in the presence and absence of Lp-PLA2 + + and in a the as the of the PC in the of three of PC that are to be the of oxidative of PC The to species a range m/z and oxidized to be products of of polyunsaturated acyl present in in of species but in oxidation oxidation significantly of saturated and species a of in to in of the and polyunsaturated species oxidation of species m/z of the and PC in the range m/z 594-666 in and in that are to truncated products of polyunsaturated fatty PC species oxidized The of Lp-PLA2 during LDL the possible actions of Lp-PLA2 during LDL oxidation by including an inhibitor of the enzyme in the oxidation the are in of and The of Lp-PLA2 on levels of the three classes of PC whose enhanced during oxidation are in of and but by + that these are the major products of Lp-PLA2 The presence of inhibitor on the of the and polyunsaturated the PC species in the m/z 594-666 of the whose levels by enhanced by in the presence of inhibitor in and in + This that of these peaks in that are substrates of Lp-PLA2. The inhibitor enhanced of the mass PC species of LDL the in these species less that for the m/z products in + suggesting that species the of the PC in are less by Lp-PLA2 during LDL and of oxidized phosphatidylcholine species in oxidized + + oxidized PC PC in a mass analysis of oxidized LDL in m/z LTQ Orbitrap in the m/z in lipid LDL oxidized in the presence of peaks for oxidized PC species and possible are in and together with the mass of the PC species Harrison K.A. Davies S.S. Marathe G.K. McIntyre T. Prescott S. Reddy K.M. Falck Murphy R.C. J. Mass 2000; PubMed Scopus Google Scholar). E. Deng Y. M. P.J. Salomon R.G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google of PC in LDL by LTQ Orbitrap Mass analysis by as of PC species and oxidized PC species with the species have mass PC species they we to the of PC and the products of LDL oxidation by accurate mass measurements of species using the LTQ Orbitrap mass an of for the oxidized PC accurate mass analysis of peaks in the range m/z Of the many peaks the abundant an with an truncated and the as a oxidized PC The to a PC with an of mass measurements for the peaks they are PC have used a analysis to for low m/z PC oxidation products in and these are in predominant for of the peaks in the and these indicating that they truncated PC LTQ Orbitrap analysis that the peaks m/z and and and an the of these species significantly in the presence of these peaks represented in species with oxidized fatty the PC species with polyunsaturated substituents as PC is a to the PC species m/z The PCs the peaks identified in the m/z an + with in the The of the have been to the of the PC The and + of the PC + a of an to an oxidized PC with an of There of in the There of an oxidized species in the + that mass analysis has to for the m/z PC oxidation products in mass and for these oxidation products are in the predominant mass in the mass to PC species of PC in oxidation of LDL a of PC we to oxidized species could be in of peaks with for the of oxidized PC species identified by of these identified by mass by LTQ Orbitrap mass spectrometry mass PC peaks in plaque, with a of and species to LDL and with a mass m/z A of peaks with of species of oxidized PC in plaque by mass There and to PC species and There oxidized and PC species in plaque of these m/z less oxidized some of these oxidized in to the major oxidized plaque PC species in the low mass range with both and a in the composition and concentration of oxidized PC species in these and of the of the species of accurate mass analysis of of mass m/z in plaque LTQ Orbitrap mass spectrometry of the lipid of these plaque the of oxidized species with PC A possible role for Lp-PLA2 in development and progression of has been by indicating that circulating levels of the enzyme are a strong independent predictor of cardiovascular disease (1Packard C.J. O'Reilly D.S. Caslake M.J. McMahon A.D. Ford I. Cooney J. Macphee C.H. Suckling K.E. Krishna M. Wilkinson F.E. Rumley A. Lowe G.D. N. Engl. J. Med. 2000; 343: 1148-1155Crossref PubMed Scopus (769) Google Scholar, 2Caslake M.J. Packard C.J. Suckling K.E. Holmes S.D. Chamberlain P. Macphee C.H. Atherosclerosis. 2000; 150: 413-419Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 3Koenig W. Khuseyinova N. Lowel H. Trischler G. Meisinger C. Circulation. 2004; 110: 1903-1908Crossref PubMed Scopus (283) Google Scholar, 4Oei H.H. van d.M.I. Hofman A. Koudstaal P.J. Stijnen T. Breteler M.M. Witteman J.C. Circulation. 2005; 111: 570-575Crossref PubMed Scopus (395) Google Scholar) and by evidence that the enzyme is in atherosclerotic and may be more in and inflammatory regions of E. Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar, M. A. K.G. P. S. Suckling K.E. C.H. Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar). A major of Lp-PLA2 in the plaque is of modified phospholipids during oxidation of LDL within the The products of are the and oxidized non-esterified fatty both of have been to pro-inflammatory roles within the plaque, suggesting a strong rationale for therapy in Macphee C.H. 2001; PubMed Scopus Google Scholar, A. Macphee C. Arterioscler. Thromb. Vasc. Biol. 2005; PubMed Scopus Google Scholar). the possible of Lp-PLA2 (and of in the have been we have used mass spectrometry to the in PC in LDL oxidation with have used an inhibitor of Lp-PLA2, present during the oxidation to species that are substrates and products of Lp-PLA2 in oxidized LDL. have used a of m/z to the in PC of LDL oxidation in are in we that oxidation to a of the peaks to PC species with polyunsaturated fatty acyl substituents and a of to PC species with the levels of PCs and saturated substituents are by the is clear the analysis of the that a of the PC that is oxidized during the is modified species that the The for the is that many of the oxidized have with the present in the LDL A. C. H. A. H. 2001; PubMed Scopus Google Scholar), it is the of the to to some of many m/z peaks to three classes of that are to be products of PC oxidation. the levels of saturated and are significantly enhanced in with LDL. these species be the abundant products of PC by as these fatty substituents are abundant the of suggesting they may be by Lp-PLA2 on modified PCs during LDL oxidation. Lp-PLA2 is by enzyme the C. D.C. 1999; 38: PubMed Scopus Google Scholar). Lp-PLA2 has phospholipids with sn-2 substituents that of K.E. Prescott S.M. McIntyre T.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). with modified sn-2 substituents substrates for Lp-PLA2 PCs, and it is that of Lp-PLA2 on these oxidation products is a major of the by LDL oxidation. The enzyme is with LDL in human where it with a of McIntyre T.M. M.E. Prescott S.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D. McIntyre T.M. Prescott S.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), and it with LDL during the been to the that is by Lp-PLA2 during LDL oxidation by including an Lp-PLA2 inhibitor during the the presence of the of suggesting that the of by Lp-PLA2 during oxidation. of by has been in LDL to oxidation for C.H. K.E. D. D.S. Suckling K.E. J. 1999; PubMed Scopus Google Scholar). The for is that a low of of Lp-PLA2 during LDL oxidation in in the levels the of the used is as with with polyunsaturated substituents is modified during the LDL oxidation is in the in the in with the levels of these are significantly enhanced by the presence of during the oxidation as they are in by Lp-PLA2 during oxidation. with the in by the presence of in the levels of the second of PC oxidation products, species represented by peaks in the m/z and we have PC The in and oxidized PC in of by the major LDL oxidized in the presence and absence of inhibitor and are the that This is clear evidence that the 594-666 by LTQ Orbitrap analysis as modified polyunsaturated fatty PC are efficient substrates for Lp-PLA2. This identifies a of present in human LDL that a major of of oxidized fatty during LDL oxidation. The presence of levels of these within atherosclerotic in with the of Lp-PLA2 be an in plaque A of have identified and of a m/z in oxidized LDL K.A. Davies S.S. Marathe G.K. McIntyre T. Prescott S. Reddy K.M. Falck Murphy R.C. J. Mass 2000; PubMed Scopus Google Scholar, E. Deng Y. M. P.J. M. R.L. Salomon R.G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) and atherosclerotic E. Deng Y. M. P.J. M. R.L. Salomon R.G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, J. G. Salomon R.L. Arterioscler. Thromb. Vasc. Biol. 2003; 23: PubMed Scopus Google Scholar). Harrison K.A. Davies S.S. Marathe G.K. McIntyre T. Prescott S. Reddy K.M. Falck Murphy R.C. J. Mass 2000; PubMed Scopus Google Scholar) phospholipids oxidized LDL by and identified of an m/z a as and The of both these is both could be major of the abundant by the LTQ Orbitrap in oxidized LDL. J. G. Salomon R.L. Arterioscler. Thromb. Vasc. Biol. 2003; 23: PubMed Scopus Google Scholar), used to in an of phospholipids oxidized LDL human atherosclerotic lesions, that a major of the m/z in oxidized LDL and human atherosclerotic lesion to be that with are of the m/z in oxidized human in LDL and oxidation could for LTQ Orbitrap analysis that a of the mass m/z in present in to a PC species mass analysis that the m/z peaks in the whose levels significantly during LDL oxidation as to oxidized is to that oxidized PC species with suggesting that they to of the species we in oxidized LDL and have been identified by of oxidized PC species M. T. T. M. A. Inoue K. Mass 2004; PubMed Scopus Google Scholar). substituents of these oxidized PCs identified in in The of these that a and an oxidized of + and m/z of + for and M. T. T. M. A. Inoue K. Mass 2004; PubMed Scopus Google Scholar). analysis of peaks and in for and in they have substituents of that the we in oxidized LDL are to these the oxidized PCs quantitatively the abundant PC products of LDL oxidation it is clear the of that they are less efficient as substrates for Lp-PLA2 are the oxidized PCs it has been that are PC by the of Lp-PLA2 in human A. F.E. McIntyre T.M. Prescott S.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a for PC with and for and Lp-PLA2 to the non-esterified a on and PC in of The for is but the that non-truncated oxidized PC are to by Lp-PLA2 a the truncated products of PC oxidation A. F.E. McIntyre T.M. Prescott S.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of identification of Lp-PLA2 substrates in oxidized LDL is by the LTQ Orbitrap mass spectrometric analysis of lipid human of the oxidized PC of LDL oxidized in the presence of and that of human plaque some oxidized PC species have been in + and in plaque and particular some of the more abundant species in + of both the and and oxidized PCs are major of many of the plaque lipid be that these are the of it is possible that many of the accurate mass peaks are more species of oxidized PC that are and the species the peaks in + and in of the of PC species that constitute the oxidized PC peaks and of the of that + and PCs of species with This constitute an of in of the oxidized fatty as potentially the of C.H. K.E. D. D.S. Suckling K.E. J. 1999; PubMed Scopus Google Scholar). we have the PC in human LDL and present oxidation with both in the presence and absence of an inhibitor of Lp-PLA2. oxidation in the of a of and PC with the of these to oxidative a of these modified as a of formation by oxidized PCs, we enhanced of species and classes of oxidized PC by accurate mass measurements using an LTQ Orbitrap Mass in oxidized LDL. of the Lp-PLA2 during oxidation identified saturated and mono-unsaturated and oxidized PCs as the major products and of the enzyme in oxidized LDL. PCs that oxidative to be less efficient substrates for Lp-PLA2 but quantitatively the abundant PC products of LDL oxidation major to by Lp-PLA2. plaque to many oxidized PC species of the as identified in LDL oxidized in the presence of Lp-PLA2 inhibitor as some in + the and composition of oxidized PC of the increasing evidence of a role for Lp-PLA2 in development and progression of atherosclerotic lesions, it be of to these in vulnerable (and in vulnerable regions of as as in the of potentially vulnerable PC substrates and products of Lp-PLA2 have the potential to as markers of atherosclerotic disease progression as as of response to potential Lp-PLA2 inhibitor therapy. are to and for and with
Davis et al. (Mon,) studied this question.