(Circulation. 1999;99:2227-2230.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Immunolocalization of ß2-Glycoprotein I (Apolipoprotein H) to Human Atherosclerotic Plaques
Potential Implications for Lesion Progression
From the Research Unit of Autoimmune Diseases (J.G., B.G., Y.L., Y.S.), Department of Medicine B; Institute of Lipid and Atherosclerosis Research (D.H.), Institute of Pathology (A.A., I.B., J.K.); and Department of Vascular Surgery (J.S.), Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel.
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Abstract |
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Background—ß2-Glycoprotein I (ß2GPI) is a major antigenic target of antiphospholipid antibodies, which possesses natural anticoagulant properties. The aim of the present study was to determine its presence and localization within human atherosclerotic plaques and to study its association with endothelial cells and monocyte macrophages in vitro.
Methods and Results—Human atherosclerotic lesions were obtained after carotid endarterectomies and studied immunohistochemically with anti-ß2GPI as well as antibodies to CD4/CD8, macrophages, and adhesion molecules. In vitro, human umbilical vein endothelial cells (HUVECs) and U937 (myelomonocytic cell line) cells were investigated for their ability to associate with radiolabeled ß2GPI. We found ß2GPI to be abundantly expressed within the subendothelial regions and intimal-medial borders of human atherosclerotic plaques and to colocalize with CD4-positive lymphocytes. This observation was confirmed by Western blot applied on homogenates of atherosclerotic lesions with anti-ß2GPI antibodies. Both HUVECs and U937 cells bound labeled ß2GPI, and the process was inhibited by oxidized LDL and not by native LDL.
Conclusions—The abundant presence of human ß2GPI within the lesions, its association with endothelial cells and macrophages, and its colocalization with CD4-positive lymphocytes suggests that it may serve as a target for an immune-mediated reaction that can influence lesion progression.
Key Words: atherosclerosis • glycoproteins • antibodies • lipoproteins
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Introduction |
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The multifactorial determinants that are involved in the development and progression of atherosclerosis have received increasing attention in recent years.1 Accordingly, the role of autoimmune factors has attracted intensive research aimed at defining the autoantigenic materials expressed within plaques that may influence the fate of lesions.2 Candidate proteins that have been mentioned include modified forms of LDL,3 heat shock proteins (reviewed in Reference 44 ), and ß2-glycoprotein I (ß2GPI).5
ß2GPI is a highly glycosylated plasma protein with an approximate molecular weight of 50 kDa that avidly binds negatively charged surfaces and substances (ie, heparin, DNA, dextran sulfate, anionic phospholipids, and apoptotic cells) (reviewed in Reference 66 ). ß2GPI contains 5 short consensus repeat domains, and its partial association with various lipoproteins results in its synonymous designation as apolipoprotein H. The recent interest in ß2GPI results from the observation that it serves as a major antigenic target of thrombosis-associated antiphospholipid antibodies (aPL).6
The physiological role of ß2GPI is still obscure, yet it possesses several properties that may bear relevance to progression of human atherosclerotic plaques (summarized in Reference 66 ): (1) it binds activated platelets and apoptotic cells (on exposure of inner-membrane phosphatidylserine); (2) it inhibits intrinsic blood coagulation pathway and ADP-dependent platelet aggregation; (3) it serves a requisite role in the activation of endothelial cells induced by aPL; and (4) it may assist in mediating clearance of senescent cells and foreign particles from circulation.
We have recently shown that immunization of LDL receptor–deficient mice with ß2GPI results in acceleration of aortic fatty streaks.5 The aortic sinus from the mice was infiltrated by CD4 lymphocytes. In the present study, we observed that ß2GPI was present in atherosclerotic plaques, and we defined its relationship with prevailing immunopotent cells. We next reinforced the findings in vitro by demonstrating the interaction of ß2GPI with cellular components of human plaques.
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Methods |
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Antigens and Antibodies
Human ß2GPI was purified as previously described.7 Oxidized LDL (oxLDL) and native LDL (nLDL) were prepared from plasma of healthy subjects as previously described.5
Antibodies used for immunohistochemistry and Western blotting were as follows: polyclonal mouse and rabbit anti-ß2GPI antibodies generated by immunization of the animals with human ß2GPI and affinity purified against the respective antigen; monoclonal mouse anti-ß2GPI antibodies (Cof-18 and Cof-21), kindly provided by Professor Takao Koike (Sapporo, Japan); anti-macrophage antibodies (CD68, clone PG-M1), anti–VCAM-1 (CD106, clone 1.4C3), and anti–E-selectin (CD62E, clone 1.2B6), all from Dako; and anti-CD4 (clone Z058), anti-CD8 (clone SPV-T8), and anti–ICAM-1 (CD54, clone MY13), all from Zymad.
Tissue Samples
Samples of human atherosclerotic plaques were obtained from
patients after carotid endarterectomy (n=5).
Additional frozen sections of human carotid plaques (n=9) and normal
carotid arteries (n=5) were obtained after postmortem procedures on
humans who died of noncardiac causes.
Immunohistochemical Study of Human Lesions
Immunohistochemical staining for human ß2GPI was performed on
5-µm-thick frozen sections of human carotid plaques. After fixation
with methanol and acetone, sections were blocked with nonimmune rabbit
and goat sera, followed by incubation with CAS blocking reagent.
Subsequently, the primary antibody (either of the anti-ß2GPI
antibodies; 20 µm/mL) was added for 1 hour at room temperature.
After washing, biotinylated affinity-purified goat anti-mouse/rabbit
antibodies (Jackson) were added. The slides were then incubated with
0.3% H2O2, followed by
additional rinses and incubation with streptavidin-peroxidase conjugate
(Jackson) for 30 minutes at room temperature. The slides were developed
with 3-amino-9 ethylcarbazole substrate (Dako) for 15 minutes
and counterstained with hematoxylin. As a control antibody, we used
normal mouse/rabbit IgG.
Immunoblotting for Detection of ß2GPI in
Human Plaques
Fresh human atherosclerotic plaques were obtained within 1
hour after carotid endarterectomy and placed
immediately in sterile PBS with 5 U/mL heparin at 4°C. The plaques
were separated from adherent surrounding tissues and blood clots, after
which the tissues were extensively washed until no contaminating blood
was observed. The tissue was then homogenized (polytron) in
PBS containing 2 mmol of a protease inhibitor (ie,
PMSF; Sigma). The homogenate was stirred for 2 hours
at 4°C. After centrifugation, the supernatant was
used for detection of the presence of ß2GPI. Supernatants of the
respective plaques and of nonlesioned arteries were applied on 10%
acrylamide SDS gel under reduced conditions, transferred to
nitrocellulose paper, and probed with anti-ß2GPI antibody. As a
control marker, we used human ß2GPI.
Association of Labeled ß2GPI With Human U937 Myelomonocytic Cell
Line and HUVECs
U937 (a monocyte/macrophage-like cell line) cells were
grown in complete culture medium (RPMI supplemented with 10% fetal
calf serum). Twenty-four hours before the experiments, the cells were
washed with sterile PBS and transferred to serum-free medium. Cells
(2x106) in RPMI with 1% BSA (in triplicates)
were incubated with 125I-ß2GPI (40 000 cpm)
alone or in the presence of nonlabeled ß2GPI, nLDL, or copper-oxLDL
(all 200 µg/mL) for 3 hours at 37°C in a 5%
CO2 incubator. After extensive washings with PBS,
cells were lysed with 2.5N NaOH, and residual radioactivity was
determined by a 
-counter.
Human umbilical vein endothelial cells (HUVECs) were isolated from normal-term umbilical cord veins by collagenase perfusion and cultured in 6-well plates under standard conditions.8 Twenty-four hours before the experiments, cells were washed and incubated in serum-free RPMI. The cells were detached by mechanical scrapping and resuspended in RPMI 1640 supplemented with 1% BSA. The assay for ß2GPI association was continued as described for the U937 cells.
Statistical Analysis
Calculations were done by ANOVA.
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Results |
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We found ß2GPI to be expressed in all slides containing atherosclerotic lesions. Immunoperoxidase staining revealed the presence of ß2GPI scattered in most areas of the lesions; however, it was most abundantly observed in the subendothelial regions and in the intimal-medial junction (Figure 1
, A and B). Staining was observed with
both the polyclonal and monoclonal anti-ß2GPI antibodies, which
recognize distinct epitopes in native structure of human ß2GPI. No
staining was evident with control primary or secondary antibodies
(Figure 1C).
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We also found that CD4-positive lymphocytes densely infiltrated the areas in which ß2GPI was expressed, whereas a relative paucity of CD8-positive cells was evident. When we applied antibodies to adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and E-selectin), we found that they were more equally distributed throughout the lesions and did not colocalize with ß2GPI.
To confirm the presence of ß2GPI in the lesions, taking into account the shortcomings of the immunohistochemical study, we used Western blot. Special care was taken to dispose of potential contamination of the lesions with serum ß2GPI by repeated washings before the extraction. We confirmed the presence of ß2GPI by observing a clear band in the 50-kDa region (data not shown).
Because endothelial cells and monocyte-derived
macrophages are among the principal cells of atherosclerotic
lesions, we wished to investigate the possibility that these cells were
involved in ß2GPI "consumption"/association. We found that
125I-ß2GPI was rapidly taken up by U937 cells.
When incubated with oxLDL (200 µg/mL), binding of
125I-ß2GPI was inhibited by 
56%
(P<0.0001), whereas only 17% inhibition was observed with
nLDL (P=NS) (Figure 2A).
Similar results were obtained with HUVECs, namely, ß2GPI was
significantly inhibited by oxLDL (53.4%; P<0.0001) and to
a lesser extent by nLDL (13.6%; P=NS) (Figure 2B).
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Discussion |
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The aim of the present study was to determine the presence and localization of ß2GPI in human atherosclerotic lesions. We used 2 independent methods for immunodetection and lent support to our observations by exploring an association of ß2GPI with cellular constituents of human lesions in vitro.
We have shown that ß2GPI is abundantly present in human atherosclerotic plaques from carotid arteries. Although randomly expressed in the different layers of the plaque, it was found to be most prominent in subendothelial regions and in the intimal-medial border of the lesions. ß2GPI colocalized with CD4-positive lymphocytes, whereas CD8-positive cells were rare. Western blotting confirmed the presence of ß2GPI within the atherosclerotic lesions.
When U937 cells and HUVECs were assayed for their association with
ß2GPI, we found that both cell types, which represent
principal cellular components of human lesions, were able to
incorporate the radioiodinated protein. Interestingly,
copper-oxLDL but not nLDL was highly specific in inhibiting the uptake
of labeled ß2GPI in both cell sources. Because ß2GPI is a normal
protein component that exists in the circulation, we washed the tissue
specimens extensively and allowed the cultured cells to remain in
serum-free conditions (devoid of ß2GPI) for 
24 hours before
performance of the assays.
The significance of the detection of human ß2GPI within human plaques can be determined with certainty only after a more elaborate understanding of the functional role of this protein has been achieved. There is evidence that ß2GPI, which is principally synthesized by the liver, may act as a natural anticoagulant and possess antiatherogenic properties.9 This notion is indirectly supported by the observation that generation of an immunologically induced anti-ß2GPI response (antagonizing the plasma protein) is associated with enhanced early atherosclerosis.5
However, when circulating autoreactive anti-ß2GPI cells or anti-ß2GPI antibodies are present and encounter their target antigen within preexisting lesions, they may contribute to acceleration of the ongoing local inflammatory reaction. The establishment of an immune response to ß2GPI could be understood in view of the observation that the protein can be taken up and perhaps processed in a major histocompatibility complex–dictated manner by antigen-presenting cells (eg, endothelial cells and macrophages). By analogy, Stemme et al10 were recently able to obtain T-cell lines from human atherosclerotic plaques that recognize oxLDL. Such T cells are likely to derive from the circulation and are probably capable of secreting proinflammatory cytokines that may influence atherogenesis. These findings are supported by studies that show a requisite role of ß2GPI in the activation of endothelial cells and platelets by aPL,11 12 13 and thus reinforce its role as a target of immune-mediated attack when presented within atherosclerotic lesions.
In conclusion, ß2GPI is abundantly expressed in human atherosclerotic lesions and can be incorporated by endothelial cells and monocyte/macrophages. The results of the present study demonstrate that further investigation of the potential implications of local ß2GPI accumulation on the progression of atherosclerosis is needed.
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Footnotes |
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Reprint requests to Yehuda Shoenfeld, Department of Medicine B, Sheba Medical Center, Tel-Hashomer 52621, Israel.
Drs George and Harats contributed equally to this article.
Received October 30, 1998; revision received March 5, 1999; accepted March 8, 1999.
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vicinity of atherosclerotic lesions, thereby promoting atherogenesis.
[Abstract/Free Full Text]
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