Expression of SR-PSOX, a Novel Cell-Surface Scavenger Receptor for Phosphatidylserine and Oxidized LDL in Human Atherosclerotic Lesions

Abstract

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. 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). 10Human 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 Methods Tissue SamplesFresh frozen sections (6 m) 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 percutaneou...

Regulated Shedding of Transmembrane Chemokines by the Disintegrin and Metalloproteinase 10 Facilitates Detachment of Adherent Leukocytes

“…Although there is growing in vivo and in vitro evidence for their involvement in promoting monocyte recruitment into inflamed tissue such as atherosclerotic lesions (17,18), there is little knowledge of how shedding can influence the activity of transmembrane chemokines. By shedding of transmembrane chemokines, ADAM proteases could in general decrease the adhesiveness of endothelial cells for leukocytes.…”

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

“…Both CXCR6 and its ligand CXCL16 have been implicated in the pathogenesis of atherosclerosis by virtue of their expression within the atherosclerotic lesions of humans and apolipoprotein Edeficient mice [8,24]. Recent data from studies using mice deficient in either CXCR6 or CXCL16 support a role for both ligand and receptor in atherogenesis [25,26].…”

“…Membrane-bound, it serves as a scavenger receptor for phosphatidylserine and oxidised low-density lipoprotein [6], and facilitates the phagocytosis of bacteria [7]. Immunohistochemical analysis suggests that CXCL16 is expressed by lipid-laden macrophages in the intima of atherosclerotic plaques and by valvular and neocapillary endothelial cells in patients with infective endocarditis, suggesting a role in the pathogenesis of both diseases [8,9]. Membrane-bound CXCL16 also facilitates the firm adhesion of cells expressing the G protein-coupled receptor CXCR6, such as activated T cells and NKT cells [10].…”

Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis

“…Firststrand complementary DNA (cDNA) was synthesized using oligo(dT) [12][13][14][15][16][17][18] primers (Amersham Pharmacia Biotech, Piscat-away, NJ) and SuperScript II reverse transcriptase (Invitrogen). The amount of cDNA for amplification was adjusted to the amount of RNA measured by optical density meter as well as ␤-actin polymerase chain reaction (PCR) products, using serially diluted cDNA.…”