Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions

The relationships between oxidation-specific epitopes (OSE) and lipoprotein (a) Lp(a) and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools, and the necrotic core, and they were most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans. The relationships between oxidation-specific epitopes (OSE) and lipoprotein (a) Lp(a) and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools, and the necrotic core, and they were most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans. adaptive intimal thickening apolipoprotein (a) early fibroatheroma, H and E, hematoxylin and eosin intimal xanthoma late fibroatheroma, Lp(a), lipoprotein (a) malondialdehyde-lysine oxidation-specific epitope oxidized phospholipid pathologic intimal thickening plaque rupture smooth muscle cell saphenous vein graft thin cap fibroatheroma Oxidative pathways in the subendothelial space activate pro-inflammatory, immunogenic, and atherogenic processes, resulting in endothelial dysfunction, plaque growth and destabilization, platelet activation, and thrombosis, ultimately leading to clinical events (1Miller Y.I. Choi S.H. Wiesner P. Fang L. Harkewicz R. Hartvigsen K. Boullier A. Gonen A. Diehl C.J. Que X. et al.Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.Circ. Res. 2011; 108: 235-248Crossref PubMed Scopus (454) Google Scholar). A variety of oxidation-specific epitopes (OSE) are generated during oxidative modification of plaque components. These epitopes are not only expressed on modified lipoproteins but also on apoptotic cells and proteins in the extracellular matrix of atherosclerotic vessels (2Chang M.K. Binder C.J. Miller Y.I. Subbanagounder G. Silverman G.J. Berliner J.A. Witztum J.L. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.J. Exp. Med. 2004; 200: 1359-1370Crossref PubMed Scopus (280) Google Scholar). Extensive experimental data exists defining the role of oxidation in both progression and regression of atherosclerosis. Atherosclerotic lesions of hypercholesterolemic animal models, which represent primarily early and intermediate stage atherosclerosis, contain significant amounts of OSE, often in proportion to plaque burden. OSE in the vessel wall of atherosclerotic animals can also be imaged with nuclear and magnetic resonance techniques using murine and human oxidation-specific antibodies, such as MDA2, E06, and IK17 (3Briley-Saebo K.C. Shaw P.X. Mulder W.J. Choi S.H. Vucic E. Aguinaldo J.G. Witztum J.L. Fuster V. Tsimikas S. Fayad Z.A. Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes.Circulation. 2008; 117: 3206-3215Crossref PubMed Scopus (146) Google Scholar–5Briley-Saebo K.C. Nguyen T.H. Saeboe A.M. Cho Y.S. Ryu S.K. Volkova E.R. Dickson S. Leibundgut G. Wiesner P. Green S. et al.In vivo detection of oxidation-specific epitopes in atherosclerotic lesions using biocompatible manganese molecular magnetic imaging probes.J. Am. Coll. Cardiol. 2012; 59: 616-626Crossref PubMed Scopus (45) Google Scholar). Dietary interventions in hypercholesterolemic animals that promote regression result in more rapid removal of OSE than apoB, which occurs prior to plaques diminishing significantly in size, and is associated with markers of plaque stabilization, such as increased collagen and smooth muscle cell (SMC) expression, and a decrease in reactive oxygen species and macrophages (6Aikawa M. Sugiyama S. Hill C.C. Voglic S.J. Rabkin E. Fukumoto Y. Schoen F.J. Witztum J.L. Libby P. Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma.Circulation. 2002; 106: 1390-1396Crossref PubMed Scopus (192) Google Scholar–8Torzewski M. Shaw P.X. Han K.R. Shortal B. Lackner K.J. Witztum J.L. Tsimikas S. in vivo of oxidation-specific antibodies in plaque with plaque 2004; PubMed Scopus Google Scholar). of animal data on the of OSE and atherosclerosis, is to clinically ruptured plaques. a of the presence of OSE in human lesions not been to the of was to the presence and of OSE in of human atherosclerotic lesions, coronary lesions, carotid endarterectomy and from carotid and saphenous vein graft protection have significant clinical with the in the clinical and of oxidative molecular and and targeting S. A. Hartvigsen K. E. Shaw P.X. M. et oxidation-specific antibodies cell and atherosclerosis Am. Coll. Cardiol. 2011; PubMed Scopus Google G. M. S. A. reduces Am. Coll. Cardiol. PubMed Scopus Google as of with coronary artery were as E.R. R. et of to plaque in sudden coronary Am. Coll. Cardiol. PubMed Scopus Google Scholar). were by the presence and type of and intimal lesions, pathologic intimal early and late fibroatheroma, thin cap fibroatheroma and plaque lesions from and death were prior to oxidation prior to also carotid endarterectomy specimens from clinically The specimens were and in from distal protection devices during of carotid arteries and coronary The was in of and lipid and for as carotid endarterectomy specimens as was sections and for in on for in on in for of the specimens was and sections were on and immunostained as coronary were on and with hematoxylin and eosin and and the modified as A. R. of coronary in 2002; PubMed Scopus Google Scholar). In a be plaque of plaque lesions that were to lipid were cell lesions were as of macrophages in the presence of significant extracellular lipid A. Y. R. of apoptotic macrophages the of plaque rupture in sudden coronary PubMed Scopus Google Scholar). Lipid pathologic intimal thickening of a matrix with lipid and of and in the These were often by macrophage cell the of necrotic with presence of apoptotic macrophage and presence of with of matrix A. Y. R. of apoptotic macrophages the of plaque rupture in sudden coronary PubMed Scopus Google Scholar). The presence of macrophages the cap of early and late fibroatheroma, thin cap and ruptured plaques. The plaque type coronary artery was as adaptive intimal thickening intimal xanthoma early fibroatheroma late fibroatheroma fibroatheroma and plaque rupture were according to a modification of the R. A. from sudden coronary a for atherosclerotic PubMed Scopus Google Scholar). The between early and late fibroatheroma was as R. A. from sudden coronary a for atherosclerotic PubMed Scopus Google the of matrix and late A. M. R. et and progression of coronary Med. PubMed Scopus Google Scholar). antibodies were in to the presence of apolipoprotein OSE, and is murine antibody that the of human Witztum J.L. S. of the lipoprotein of B. by a PubMed Google Scholar). to lipoproteins and also to of on is minimally to modified during oxidation by to in is a murine antibody from that the of oxidized phospholipids and the OxPL is to of OxPL occurs the reactive oxidized such as generated on the the phospholipids are The is in and is the recognized by a variety of OxPL with by such as and not recognize to was present as the of OxPL A. P. Harkewicz R. Hartvigsen K. Green Witztum J.L. as a pattern recognition for Lipid Res. PubMed Scopus Google P. S. Witztum J.L. of antibody recognition with the of oxidized of and 2002; PubMed Scopus Google Scholar). to with of in which MDA as a on a a variety of proteins S. Witztum J.L. MDA2, atherosclerotic lesions in Cardiol. PubMed Scopus Google Scholar). IK17 is a human generated with that also to MDA with but to be more for as not to P.X. S. Tsimikas S. M.K. Silverman G.J. Witztum J.L. of oxidized by macrophages and to atherosclerotic lesions in PubMed Scopus Google of MDA modification is IK17 a more MDA have not IK17 also to whereas epitope to be MDA that is present on both and not is a murine antibody the on and not with S. Han K.R. Shortal B. Miller E.R. A. Witztum J.L. coronary in in oxidized phospholipids and and to oxidized 2004; PubMed Scopus Google Scholar). were than sections were with antibodies MDA2, E06, and of and The detection of antibodies to was using the antibody with antibodies to sections for antibody IK17 were with a of in to IK17 IK17 was in and for was using antibody for and with the of cell sections were immunostained for macrophages with and with antibodies were using The of MDA2, E06, and IK17 and macrophage was and plaque was on a of of of of of coronary sections were using on with with with of OSE for antibody of distal protection devices were of the variety was to a lipid with lipid of was a of and were as and the were a for the was a using a and the was to and was using a with a was a using a A of with a of was for The was to a for and of were using of the were using with a as and X. Nguyen M. Harkewicz R. Witztum J.L. Tsimikas S. et and lipoproteins in macrophages PubMed Scopus Google Scholar). of the were using the and The is of a by can be in the of the in a and the by in a A of is in which can be in a In the by of is the with in the were the and between the lesions were with by for was to the between macrophages and A of was The patterns and by plaque in plaque are in The macrophage cells and the necrotic core, as detected by was primarily in early lesions in lipid and in amounts in and the necrotic core. macrophages did not for with detected by MDA2, a pattern of as but in OxPL detected by E06, were strongest in macrophage-rich areas, lipid pools, and the necrotic core. 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IK17 epitopes are in the necrotic and absent of a thin cap fibroatheroma thin cap a late necrotic core. are absent in the cap but present in the and is of macrophages in the thin cap and necrotic core. is to the necrotic and areas, and MDA epitopes are in areas, the of is OxPL are primarily present in the cap in macrophages and in the extracellular in the of the necrotic core. is for apo(a) in the cap and of the necrotic core, in the extracellular IK17 is in the late necrotic core. of plaque rupture a coronary with cap and are present in the but not in the In is of macrophages in the cap and necrotic core. for is MDA epitopes are expressed in the cap cells and extracellular matrix and necrotic core. OxPL are primarily to macrophages in the of the necrotic core. is to apo(a) in the cap the necrotic core. IK17 epitopes are present only in the late necrotic core. also carotid endarterectomy specimens that were and in carotid lesions findings to with the coronary lesions. of of a carotid with a necrotic and presence of macrophages the presence of OSE is in to the findings in the coronary arteries, apoB and MDA epitopes were to the of necrotic core. OxPL, apo(a) and IK17 epitope was macrophages and the necrotic core. for the presence of oxidized in necrotic lesions, plaque from such lesions during and by distal protection devices. The were in and lipid and by for the presence of of a and OxPL J.A. Tsimikas S. The role of oxidized phospholipids in Lipid Res. PubMed Scopus Google E. R. Y. M. L. M. et of atherogenic oxidized phospholipids macrophage cell the and is in atherosclerotic 2002; PubMed Scopus Google that with P.X. S. M.K. Silverman G.J. Witztum J.L. antibodies with the in atherosclerosis, apoptotic and PubMed Scopus Google were detected from both carotid and coronary distal protection devices that the OxPL detected in both the coronary and carotid lesions by epitopes present in vivo and not of oxidation that during of carotid endarterectomy specimens for on for in for in patterns antibodies with of prior to is the OSE and apo(a) in a of human and atherosclerotic lesions. The a differential expression of apoB-100, OSE, and apo(a) in the progression of atherosclerosis from early lesions to plaque that during early atherosclerosis are in apoB-100, apo(a), and the OSE in as lesions progress, apo(a), OxPL, and IK17 epitopes become apo(a) epitopes were present in most lesions, whereas OxPL and IK17 epitopes were associated with macrophages of the cap and the necrotic core. IK17 epitopes were most specifically associated with necrotic and plaque a was in of carotid endarterectomy the presence of OxPL in by distal protection presence in vivo in clinically plaques. These provide a for the between OSE and and the progression and of human coronary and carotid atherosclerosis. antibodies targeting lipoprotein and OSE to to human atherosclerosis, as in not only the of but also apoB of minimally oxidized and apoB of oxidized can recognize both as as epitopes on proteins in the vessel such as S. Shortal Witztum J.L. In vivo of MDA2, oxidation-specific of atherosclerotic lesions in oxidized and is to PubMed Scopus Google B. S. Witztum J.L. apolipoprotein by but not by of reactive by the PubMed Scopus Google and also been for imaging of experimental atherosclerotic lesions (3Briley-Saebo K.C. Shaw P.X. Mulder W.J. Choi S.H. Vucic E. Aguinaldo J.G. Witztum J.L. Fuster V. Tsimikas S. Fayad Z.A. 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PubMed Scopus Google S. M. B. M. C.J. S. Witztum J.L. et and from the PubMed Scopus Google Scholar). to the of and is in to but not been to S. Han K.R. Shortal B. Miller E.R. A. Witztum J.L. coronary in in oxidized phospholipids and and to oxidized 2004; PubMed Scopus Google Scholar). Apo(a) is not oxidation-specific but apo(a) and OxPL, which the atherogenic of A. A. E. Miller E.R. Binder C.J. S. et of lipoprotein as a of oxidized phospholipids in human Lipid Res. 2008; PubMed Scopus Google Scholar). IK17 is a human from a and to a epitope present on both and IK17 also been in and imaging atherosclerosis in and (3Briley-Saebo K.C. Shaw P.X. Mulder W.J. Choi S.H. Vucic E. Aguinaldo J.G. Witztum J.L. Fuster V. Tsimikas S. Fayad Z.A. Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes.Circulation. 2008; 117: 3206-3215Crossref PubMed Scopus (146) Google Scholar–5Briley-Saebo K.C. Nguyen T.H. Saeboe A.M. Cho Y.S. Ryu S.K. Volkova E.R. Dickson S. Leibundgut G. Wiesner P. Green S. et al.In vivo detection of oxidation-specific epitopes in atherosclerotic lesions using biocompatible manganese molecular magnetic imaging probes.J. Am. Coll. Cardiol. 2012; 59: 616-626Crossref PubMed Scopus (45) Google P.X. S. Tsimikas S. M.K. Silverman G.J. Witztum J.L. of oxidized by macrophages and to atherosclerotic lesions in PubMed Scopus Google Scholar). The in patterns present the antibodies that epitopes are generated during of and epitopes can be generated of present on and cell in the vessel as such as the that epitopes are generated oxidative expression of epitopes on the stage of MDA epitopes were more in early lesions, such as in and early whereas OxPL, apo(a), and IK17 epitopes were more in lesions. of the prior data with antibody were generated in and rabbit models, with early to intermediate lesions patterns both and S. S. Witztum J.L. of oxidation and apolipoprotein in atherosclerotic lesions of from PubMed Scopus Google Scholar). been to early lesions in in the B. G. for more of epitopes of oxidized lipoprotein in of with PubMed Scopus Google Scholar). in the MDA epitopes did not become more as lesions be that MDA epitopes are generated early in the of atherosclerosis and more plaque and plaque than plaque is also that is of epitopes in more have that H also MDA both in the of with and in human coronary specimens Hartvigsen K. P. M. Tsimikas S. et H epitopes and from oxidative 2011; PubMed Scopus Google Scholar). In prior of such with antibodies and but also is that and of is also that epitopes be by to that have been A. Miller E.R. A. Witztum J.L. et of and and to oxidized with markers of oxidation and and from the Lipid Res. 2011; PubMed Scopus Google Scholar). of epitopes be of the wall on macrophages In apo(a), OxPL, and IK17 epitopes were in macrophages in thin necrotic and ruptured that they more and unstable plaques. In with findings in late lesions, was also a increased expression of macrophage markers and a of with the findings of plaque the expression of apo(a), OxPL, and IK17 epitopes more plaque destabilization, and was in the stage coronary lesions in OxPL and of be to of OxPL epitopes as lesions in extracellular matrix in stage lesions of both the carotid and coronary plaque are the of in the cap for the and is present both in the macrophages of the cap and cap whereas in the necrotic core. These data in human lesions that a from early lesions to plaque rupture can only be with animal data in which most lesions are the the patterns for lesions and epitopes are expressed in animals and and are not species but to the oxidative pathways The and of the OSE is present on and such lipoproteins the they to extracellular matrix K.J. lipoprotein as the in and PubMed Scopus Google and oxidation by a variety of the presence of apoB and MDA epitopes in early lesions. As plaques progress, macrophage and activation increase, which to oxidation of resulting in progressive lipid oxidation and of OxPL and IK17 IK17 which primarily in the necrotic macrophage cells and necrotic have represent a of oxidation of MDA-related prior in to IK17 epitopes on which to MDA-related have been that they only be present in oxidized and modified proteins lesions. is to that both and IK17 to apoptotic cells and apoptotic (2Chang M.K. Binder C.J. Miller Y.I. Subbanagounder G. Silverman G.J. Berliner J.A. Witztum J.L. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.J. Exp. Med. 2004; 200: 1359-1370Crossref PubMed Scopus (280) Google P.X. S. Tsimikas S. M.K. Silverman G.J. Witztum J.L. of oxidized by macrophages and to atherosclerotic lesions in PubMed Scopus Google which are in late lesions and a to the unstable and the OxPL are to be a leading to macrophage and cell death X. Nguyen M. Harkewicz R. Witztum J.L. Tsimikas S. et and lipoproteins in macrophages PubMed Scopus Google Scholar). are to the pathways which OSE are generated in In the was that is in atherosclerotic in early lesions, and that as lesions to plaque The that apoB, apo(a), and OxPL did not that the apoB and OxPL of be and but that the apo(a) to be to the plaque and have a E. G. P. G. to of and with smooth muscle cell extracellular PubMed Scopus Google Scholar). also that and significant amounts of OxPL are in the vessel wall in and of OxPL by with the findings of the presence of in a was with apo(a) in and the of the clinical in with coronary G. J.A. S. of with the and clinical of coronary artery Cardiol. PubMed Scopus Google Scholar). as promote macrophage cell death a to plaque rupture X. Nguyen M. Harkewicz R. Witztum J.L. Tsimikas S. et and lipoproteins in macrophages PubMed Scopus Google Scholar). the of data that is and for R. A. S. S. S. et associated with lipoprotein and coronary Med. PubMed Scopus Google A. R. and increased of PubMed Scopus Google and with interventions to E. Miller E.R. Witztum J.L. Tsimikas S. to human apolipoprotein reduces and oxidized phospholipids on human apolipoprotein in 2008; PubMed Scopus Google F.J. J.L. S. et apolipoprotein for lowering of in with a PubMed Scopus Google and B. and S. data provide a rationale to both plaque progression and plaque destabilization, and they targeting oxidation have during of the coronary specimens to in sudden and have the findings in the stage lesions. the findings with the carotid as they were in and to In the pattern of OSE In the that MDA epitopes did not with and that the experimental of of carotid endarterectomy specimens in that oxidation did in the coronary did not significantly the of a of human plaque and of atherosclerosis that OSE, in detected by antibodies E06, and are and in atherosclerotic lesions and ruptured plaques. and targeting OSE, such as and imaging and applications have the clinical S. A. Hartvigsen K. E. Shaw P.X. M. et oxidation-specific antibodies cell and atherosclerosis Am. Coll. Cardiol. 2011; PubMed Scopus Google A. S. S. R. human antibodies apolipoprotein 2004; PubMed Scopus Google G. M. S. A. reduces Am. Coll. Cardiol. PubMed Scopus Google Scholar). As ultimately to clinical the data generated in provide a for clinical applications and of the the presence of OxPL distal protection devices is with prior data increased OxPL in S. Han K.R. Shortal B. Miller E.R. A. Witztum J.L. coronary in in oxidized phospholipids and and to oxidized 2004; PubMed Scopus Google and the of with to and OxPL OSE during be by oxidation-specific antibodies of of prior to such as with antibodies the human antibody which been to OSE, cell and atherosclerosis progression in atherosclerotic S. A. Hartvigsen K. E. Shaw P.X. M. et oxidation-specific antibodies cell and atherosclerosis Am. Coll. Cardiol. 2011; PubMed Scopus Google Scholar). is and not for the role of OSE in plaque progression and using human OSE antibodies and clinical be to the role of OSE in