The class A scavenger receptor (SR-A) binds modified lipoproteins and has been implicated in cholesterol ester deposition
in macrophages. The SR-A also contributes to cellular adhesion. Using SR-A
...+/+ and SR-A
â
/
â murine macrophages, we found SR-A expression important for both divalent cation-dependent and -independent adhesion of macrophages
to the human smooth muscle cell extracellular matrix. The SR-A mediated 65 and 85% of macrophage adhesion to the extracellular
matrix in the presence and absence of serum, respectively. When EDTA was added to chelate divalent cations, the SR-A mediated
90 and 95% of the macrophage adhesion without and with serum, respectively. SR-A-mediated adhesion to the extracellular matrix
was prevented by fucoidin, an SR-A antagonist. Biglycan and decorin, proteoglycans of the extracellular matrix, were identified
as SR-A ligands. Compared with control cells, Chinese hamster ovary cells expressing the SR-A showed 5- and 6-fold greater
cell association (binding and internalization) of 125 I-decorin and -biglycan, respectively. In competition studies, unlabeled proteoglycan or fucoidin competed for binding of 125 I-labeled decorin and -biglycan, and biglycan and decorin competed for the SR-A-mediated cell association and degradation
of 125 I-labeled acetylated LDL, a well characterized ligand for the SR-A. These results suggest that the SR-A could contribute to
the adhesion of macrophages to the extracellular matrix of atherosclerotic plaques.
Upon activation, platelets secrete a 120-kDa protein that competes for the binding and internalization of acetyl low density
lipoproteins (AcLDL) by macrophages. From the amino-terminal amino acid ...sequence, amino acid composition, and immunoblot analysis,
we identified the active factor in platelet secretion products as sAPP, an α-secretase cleavage product of the β-amyloid precursor
protein (APP), that contains a Kunitz-type protease inhibitor (KPI) domain. We showed that both sAPP751 (also called Nexin
II) and sAPP695, which does not contain a KPI domain, are ligands for the class A scavenger receptor (SR-A). Chinese hamster
ovary cells stably transfected to express the SR-A bound and internalized 4-fold more human platelet-derived sAPP than control
cells. The binding and internalization of sAPP were inhibited by the SR-A antagonist fucoidin. In addition, sAPP competed
as effectively as fucoidin for SR-A-mediated cell association and degradation of 125 I-AcLDL. To determine if the KPI domain is required for the binding of sAPP to the SR-A, APP751 and APP695 were expressed
in Chinese hamster ovary cells, and sAPP751 and sAPP695 purified from the medium were tested for their binding to the SR-A.
sAPP751 and sAPP695 were equally effective in competing for the cell association of 125 I-AcLDL by SR-A-expressing cells, demonstrating that the KPI domain is not essential for binding. We also found that sAPP751
is present in extracts of atherosclerotic lesions and that sAPP competes for the SR-A-mediated cell association of oxidized
low density lipoprotein. Deletion mutagenesis indicated that a negatively charged region of APP (residues 191â264) contributes
to binding to the SR-A. These results suggest that the SR-A contributes to the clearance of sAPP and that sAPP competes for
the cell association of other SR-A ligands.
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