doi: 10.1161/hq1001.096652
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Expression of SR-PSOX, a Novel Cell-Surface Scavenger Receptor for Phosphatidylserine and Oxidized LDL in Human Atherosclerotic Lesions
From the Departments of Geriatric Medicine (M.M., N.K., K.H., T.K.), Neurosurgery (H.K.), and Cardiovascular Surgery (M.H., M.K.), Graduate School of Medicine, Kyoto University, and Institute for Virus Research (T.S., S.Y.), Kyoto University, Kyoto, Japan; the Department of Neurosurgery (Y.A., I.N.), National Cardiovascular Center, Suita, Japan; and the Department of Cardiology (K.A., M.N.), Kokura Memorial Hospital, Kitakyushu, Japan.
Correspondence to Noriaki Kume, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail nkume{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Abstract—— Receptor-mediated endocytosis of oxidized low density lipoprotein (Ox-LDL) by macrophages and the subsequent foam cell transformation in the arterial intima are key events in early atherogenesis. Recently, we have identified a novel macrophage cell-surface receptor for Ox-LDL by expression cloning from a cDNA library of phorbol 12-myristate 13-acetate–stimulated THP-1 cells, designated as the scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX). Here, we examined SR-PSOX expression in human atherosclerotic lesions. Total cellular RNA and fresh frozen sections were prepared from human carotid endarterectomy specimens (from 21 patients) and directional coronary atherectomy specimens (from 11 patients). Fragments of human aortas of 2 patients without visible atherosclerotic lesions served as negative controls. Quantitative reverse transcription–polymerase chain reaction demonstrated that SR-PSOX mRNA expression was prominent in atherosclerotic lesions but undetectable in normal aortas. Immunohistochemistry showed that SR-PSOX was predominantly expressed by lipid-laden macrophages in the intima of atherosclerotic plaques in carotid endarterectomy and directional coronary atherectomy specimens, although its expression was not detectable in normal arterial wall. Double-labeled immunohistochemistry confirmed that SR-PSOX is expressed by intimal macrophages. Taken together, SR-PSOX may be involved in Ox-LDL uptake and subsequent foam cell transformation in macrophages in vivo and thus may play important roles in human atherosclerotic lesion formation.
Key Words: atherosclerosis • immunohistochemistry • lipoproteins • macrophages • receptors
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Introduction |
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Accumulation of lipid-laden foam cells derived from a monocyte-macrophage lineage in the arterial intima appears to be a key event in early atherogenesis. Several lines of evidence suggest that oxidized LDLs (Ox-LDLs) may play crucial roles in the pathogenesis of atherosclerosis.1,2 Uptake of Ox-LDL in macrophages by receptor-mediated endocytosis appears to be involved in cellular accumulation of cholesteryl ester and subsequent foam cell transformation. So far, several different cell-surface receptors, such as scavenger receptors class A (SR-A),3–5 CD36,6 SR-BI,7 CD68,8 and lectin-like receptor for Ox-LDL (LOX-1),9 have been identified to support cellular uptake of Ox-LDL; however, additional molecules may also be involved in the endocytosis of Ox-LDL. Recently, by expression cloning from a cDNA library of phorbol 12-myristate 13 acetate (PMA)-stimulated THP-1 cells, we have identified a novel cell-surface receptor for Ox-LDL, which has been designated the scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX).10
Human SR-PSOX is a 30-kDa type I membrane protein consisting of 254 amino acids, which does not share any structural homology with other Ox-LDL receptors. SR-PSOX can bind and internalize Ox-LDL but not a significant amount of acetylated or native LDL. Internalized Ox-LDL, in cells expressing SR-PSOX, was subjected to lysosomal degradation. SR-PSOX also recognizes phosphatidylserine, polyinosinic acid, and dextran sulfate but not polycytidylic acid or chondroitin sulfate. In addition to PMA-stimulated THP-1 cells, expression of SR-PSOX has also been shown on human monocyte-derived macrophages and murine thioglycollate-elicited peritoneal macrophages.10 These data demonstrate that SR-PSOX is a novel class of molecule that belongs to the scavenger receptor family; however, the relation of this novel receptor to atherogenesis has not yet been clarified.
In the present study, therefore, we have explored the expression of SR-PSOX in atherosclerotic lesions of human carotid and coronary arteries. We provide evidence that SR-PSOX is abundantly expressed by lipid-laden macrophages in the intima of atherosclerotic plaques, although its expression was not detectable in normal arterial walls.
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Methods |
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Tissue Samples
Fresh frozen sections (6 µm) were prepared from human carotid endarterectomy specimens from 21 patients who had transient ischemic attacks or minor completed strokes before their operations, and sections were also prepared from human directional coronary atherectomy specimens from 11 patients who underwent elective percutaneous coronary interventions because of angina pectoris or asymptomatic myocardial ischemia. Fragments of human aortas without visible atherosclerotic lesions were obtained from 2 patients who underwent cardiovascular surgery. These tissue samples were embedded in Tissue-Tek OCT compound (Miles Laboratories Inc), frozen in liquid nitrogen, and stored at -80°C until use. Total cellular RNA was isolated from 8 carotid endarterectomy specimens and 2 aortic tissue samples by Trizol reagent (GIBCO-BRL) after homogenization as previously described.11
Reverse Transcription–PCR Analysis
Equal amounts of total cellular RNA (250 ng) was reverse-transcribed with oligo(dT) primer by use of AMV Reverse Transcriptase (Takara). Transcribed cDNAs were used for polymerase chain reaction (PCR) with specific primers for human SR-PSOX (5'-ACTCAGCCAGGCAATGGCAAC-3' and 5'-GGTATTA-GAGTCAGGTGCCAC-3') and GAPDH (5'-CTGGTCACC-AGGGCTGCTTTT-3' and 5'-CATGAGGTCCACCACCCTGTT-3') with Ex Taq DNA polymerase (Takara). PCR products were then subjected to electrophoresis through 1% agarose gels and ethidium bromide staining.
Immunocytochemistry of COS-7 Cells Transfected With Human SR-PSOX
COS-7 cells were cultured onto Laboratory-Tek II chamber slides (Nalge Nunc) and transfected with the mammalian expression vector containing the full length of human SR-PSOX cDNA by use of LipofectAMINE Plus (GIBCO-BRL). At 48 hours after the transfection, cells were fixed for 2 minutes in cold acetone and then stained with 2 different rabbit anti-human SR-PSOX polyclonal antibodies, which we have previously generated,10 by the avidin-biotin complex peroxidase method. In brief, cells were incubated with these anti-human SR-PSOX polyclonal antibodies, followed by incubation with a biotinylated goat anti-rabbit IgG (DAKO). Endogenous peroxidase activity was blocked with methanol containing 0.3% hydrogen peroxide, after which avidin-biotin peroxidase complexes (ABC Elite Kit, Vector Labs) were added. Staining with the antibodies was visualized with 3,3'-diaminobenzidine tetrahydrochloride (Vector Labs) and then counterstained with Mayer’s hematoxylin (Wako). Untransfected COS-7 cells were immunostained with the same antibodies to serve as negative controls.
Single-Labeled Immunohistochemistry
Frozen sections were fixed for 2 minutes in cold acetone, and then immunohistochemical staining with the rabbit anti-human SR-PSOX polyclonal antibodies was performed as described above. Immunohistochemical analyses of adjacent sections with cell-type-specific antibodies were also carried out by use of anti-human CD68 monoclonal antibody (DAKO) and anti-human smooth muscle 
-actin monoclonal antibody (DAKO). Staining with nonimmune rabbit IgG (Zymed) served as a negative control. For detection of lipids accumulated in foam cells, oil-red O staining was also performed.
Double-Labeled Immunohistochemistry
For double-labeled immunohistochemistry, after sections were fixed with cold acetone, they were first incubated with the anti-human SR-PSOX polyclonal antibody and then incubated with biotinylated goat anti-rabbit IgG (DAKO), which was followed by incubation with an avidin-biotin peroxidase conjugate and then visualized with 3,3'-diaminobenzidine tetrahydrochloride (Vector Labs). Sections were subsequently incubated with the cell-specific antibodies; this incubation was followed by incubation with alkaline phosphatase–conjugated anti-mouse IgG (PharMingen) and visualized with fast red alkaline phosphatase substrate solution (Vector Labs).
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Results |
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Upregulated Expression of SR-PSOX mRNA in Human Atherosclerotic Plaques
To examine the levels of SR-PSOX mRNA expression in human atherosclerotic plaques, total cellular RNA was isolated from carotid endarterectomy specimens and normal aortic tissue samples, and then reverse transcription (RT)-PCR analyses were performed. As shown in Figure 1, SR-PSOX mRNA expression was prominent in human atherosclerotic plaques. In contrast, in the unaffected human aortas, SR-PSOX mRNA was not detectable. Amounts of GAPDH mRNA, which served as an internal control, were not significantly different. Total RNA isolated from human peripheral monocyte-derived macrophages showed RT-PCR products with the same molecular size.
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Immunoreactivity of Anti-Human SR-PSOX Polyclonal Antibodies
To explore the expression of SR-PSOX in atherosclerotic lesions by immunohistochemistry, we generated 2 different rabbit polyclonal antibodies against human SR-PSOX, which were raised by immunization with conjugates of carrier protein and synthetic peptides corresponding to extracellular (181 to 200) and intracellular (235 to 254) amino acid residues.10 Both of these polyclonal antibodies were equally bound to human SR-PSOX expressed on the cell surface of COS-7 cells, which had been transfected with human SR-PSOX cDNA but did not react with untransfected COS-7 cells. Figure 2 shows the immunocytochemistry of COS-7 cells expressing human SR-PSOX by use of 1 of the 2 polyclonal antibodies.
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Increased Expression of SR-PSOX by Intimal Macrophages in Human Carotid Atherosclerotic Lesions
Immunohistochemical staining of human carotid endarterectomy specimens with the anti-SR-PSOX antibodies showed that SR-PSOX was abundantly expressed in the intima of atherosclerotic plaques (Figure 3A). At higher magnification, SR-PSOX was found to be expressed by macrophage-like cells in the intima (Figure 3B). In fact, immunostaining with these 2 different anti-human SR-PSOX antibodies showed the same results. In addition, staining of the serial sections by cell-type–specific antibodies indicated that SR-PSOX-positive cells were mostly CD68-positive macrophages (Figure 3C) but not -actin-positive smooth muscle cells (Figure 3D). Oil red O staining of the adjacent sections showed lipid deposition in these SR-PSOX-positive macrophages in the intima of atherosclerotic lesions (Figure 3F). Furthermore, double-labeled immunohistochemistry with use of the anti-SR-PSOX and anti-CD68 antibodies confirmed that SR-PSOX was expressed by intimal macrophages (Figure 3G). In contrast, SR-PSOX expression was not detectable in normal arterial wall (data not shown).
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SR-PSOX Expression in Human Coronary Atherosclerotic Lesions
In addition to carotid atherosclerotic lesions, we have examined the expression of SR-PSOX in human coronary atherosclerotic lesions obtained by directional coronary atherectomy. As shown in Figure 4A, SR-PSOX was focally expressed by cells accumulated in the intima of atherosclerotic plaques. Immunostaining of the adjacent sections with anti-CD68 antibodies showed that these SR-PSOX-positive cells were mostly macrophages (Figure 4B), as is the case with carotid endarterectomy specimens. Oil red O staining also showed that SR-PSOX-positive cells, in fact, accumulate lipids (Figure 4C).
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Discussion |
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Several lines of evidence have shown that Ox-LDLs may play crucial roles in the pathogenesis of atherosclerosis.1,2 Ox-LDL and its lipid constituents have been shown to transcriptionally induce endothelial genes relevant to atherogenesis,12,13 and receptor-mediated endocytosis of Ox-LDLs appears to play key roles in cholesteryl ester accumulation and the subsequent foam cell transformation of macrophages or vascular smooth muscle cells. Multiple different molecules, including SR-A,3–5 CD36,6 SR-BI,7 CD68,8 and LOX-1,9 have been identified as cell-surface receptors for Ox-LDL. Previous studies have shown that macrophages accumulated in the intima of human atherosclerotic plaques can highly express SR-A14–17 as well as CD36.18 Expression of LOX-1, which was initially identified as an endothelial scavenger receptor, has also been demonstrated in human atherosclerotic lesions not only on vascular endothelial cells but also on intimal macrophages and smooth muscle cells.11 Studies with SR-A19 and CD3620 knockout mice, so far, have shown that these molecules may play significant roles, at least in part, in atherosclerotic lesion formation of hypercholesterolemic mice in vivo. In addition, these scavenger receptor family molecules, in general, have a variety of biological ligands, including apoptotic cells,21–23 bacteria,24,25 advanced glycation end product,26,27 and ß-amyloid protein,28 suggesting that these molecules may also play important roles in the pathogenesis of various diseases.
SR-PSOX is a novel class of cell-surface receptors for Ox-LDL, isolated from a cDNA library of PMA-stimulated THP-1 cells. Although SR-PSOX doses not share any structural homology with other scavenger receptor families, it can bind and internalize Ox-LDL with high affinity. In addition to PMA-stimulated THP-1 cells, expression of SR-PSOX has been demonstrated on human monocyte-derived macrophages and murine thioglycollate–elicited peritoneal macrophages in vitro.10 As shown in the present study, SR-PSOX is abundantly expressed by lipid-laden macrophages accumulated in the intima of human atherosclerotic lesions but not by endothelial cells or smooth muscle cells. Therefore, SR-PSOX may be involved in Ox-LDL uptake and subsequent foam cell transformation in macrophages and thus may play important roles in atherosclerotic lesion formation. In addition, SR-PSOX appears identical to CXCL16, a novel membrane-anchored chemokine directed to activated T lymphocytes, which express its counterreceptor CXCR6/Bonzo.29,30 Therefore, SR-PSOX might also act as a chemokine for certain subsets of T lymphocytes accumulated with macrophages in atherosclerotic lesions.
Previous studies have indicated that the regulation of scavenger receptor expression varies among different molecules. For example, tumor necrosis factor- and transforming growth factor-ß inhibit the expression of SR-A31,32 and CD3633 in macrophages, although these cytokines can induce LOX-1 expression.34,35 Peroxisome proliferator-activated receptors are transcriptional factors considered as important regulators in lipid and glucose metabolism as well as monocyte-macrophage differentiation. Peroxisome proliferator-activated receptor 
ligands can upregulate CD36 expression36 but not SR-A.37 It remains unclear whether SR-PSOX expression can be regulated by these proinflammatory stimuli or nuclear receptors. As shown in other Ox-LDL receptors, SR-PSOX might also be expressed in other cell types, including vascular smooth muscle cells, under certain pathological conditions; however, the present study shows that macrophages are the only cell type that can express SR-PSOX in human atherosclerotic lesions.
In summary, our present study provides the first evidence that SR-PSOX is abundantly expressed in lipid-laden macrophages accumulated in human atherosclerotic lesions. Further studies related to the regulatory mechanisms of SR-PSOX expression in macrophages and the pathophysiological consequences of Ox-LDL uptake through this novel receptor may provide new insights into the pathogenesis of atherosclerosis.
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Acknowledgments |
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This work has been supported, in part, by a grant from the Center of Excellence (No. 12CE2006); grants-in-aid (Nos. 11838008, 11694266, 11307018, and 32644) from the Minister of Education, Science, Sports, and Culture of Japan; grant RFTF97L00803 from the Japan Society for the Promotion of Science; and grants from the Takeda Science Foundation and the Novartis Foundation for Gerontological Research.
Received June 7, 2001; accepted July 17, 2001.
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K. Hase, T. Murakami, H. Takatsu, T. Shimaoka, M. Iimura, K. Hamura, K. Kawano, S. Ohshima, R. Chihara, K. Itoh, et al. The Membrane-Bound Chemokine CXCL16 Expressed on Follicle-Associated Epithelium and M Cells Mediates Lympho-Epithelial Interaction in GALT J. Immunol., January 1, 2006; 176(1): 43 - 51. [Abstract] [Full Text] [PDF]
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O. Quehenberger Thematic Review Series: The Immune System and Atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis J. Lipid Res., August 1, 2005; 46(8): 1582 - 1590. [Abstract] [Full Text] [PDF]
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D. R. Greaves and S. Gordon Thematic review series: The Immune System and Atherogenesis. Recent insights into the biology of macrophage scavenger receptors J. Lipid Res., January 1, 2005; 46(1): 11 - 20. [Abstract] [Full Text] [PDF]
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J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
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C. Weber, A. Schober, and A. Zernecke Chemokines: Key Regulators of Mononuclear Cell Recruitment in Atherosclerotic Vascular Disease Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 1997 - 2008. [Abstract] [Full Text] [PDF]
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S. Abel, C. Hundhausen, R. Mentlein, A. Schulte, T. A. Berkhout, N. Broadway, D. Hartmann, R. Sedlacek, S. Dietrich, B. Muetze, et al. The Transmembrane CXC-Chemokine Ligand 16 Is Induced by IFN-{gamma} and TNF-{alpha} and Shed by the Activity of the Disintegrin-Like Metalloproteinase ADAM10 J. Immunol., May 15, 2004; 172(10): 6362 - 6372. [Abstract] [Full Text] [PDF]
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D. M. Wuttge, X. Zhou, Y. Sheikine, D. Wagsater, V. Stemme, U. Hedin, S. Stemme, G. K. Hansson, and A. Sirsjo CXCL16/SR-PSOX Is an Interferon-{gamma}-Regulated Chemokine and Scavenger Receptor Expressed in Atherosclerotic Lesions Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 750 - 755. [Abstract] [Full Text] [PDF]
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P. J. Gough, K. J. Garton, P. T. Wille, M. Rychlewski, P. J. Dempsey, and E. W. Raines A Disintegrin and Metalloproteinase 10-Mediated Cleavage and Shedding Regulates the Cell Surface Expression of CXC Chemokine Ligand 16 J. Immunol., March 15, 2004; 172(6): 3678 - 3685. [Abstract] [Full Text] [PDF]
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P. Shashkin, D. Simpson, V. Mishin, B. Chesnutt, and K. Ley Expression of CXCL16 in Human T Cells Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 148 - 149. [Full Text] [PDF]
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D. Li, R. M. Singh, L. Liu, H. Chen, B. M. Singh, N. Kazzaz, and J. L. Mehta Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells Cardiovasc Res, January 1, 2003; 57(1): 238 - 243. [Abstract] [Full Text] [PDF]
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V. V. Kunjathoor, M. Febbraio, E. A. Podrez, K. J. Moore, L. Andersson, S. Koehn, J. S. Rhee, R. Silverstein, H. F. Hoff, and M. W. Freeman Scavenger Receptors Class A-I/II and CD36 Are the Principal Receptors Responsible for the Uptake of Modified Low Density Lipoprotein Leading to Lipid Loading in Macrophages J. Biol. Chem., December 13, 2002; 277(51): 49982 - 49988. [Abstract] [Full Text] [PDF]
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O. Hofnagel, B. Luechtenborg, G. Plenz, H. Robenek, and N. Kume Expression of the Novel Scavenger Receptor SR-PSOX in Cultured Aortic Smooth Muscle Cells and Umbilical Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 710 - 711. [Full Text] [PDF]
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