Inhibition of foam cell formation using a soluble CD68-Fc fusion protein.
The appearance of lipid-rich foam cells is a major feature of vulnerable atherosclerotic plaque formation. The transformation of macrophages into foam cells results from excessive uptake of cholesterol-rich particles by scavenger receptors such as CD68. We cloned a CD68-Fc immunoadhesin, a fusion protein consisting of the extracellular domain of the human CD68 and a human Fc domain, and investigated the function in vitro. Specific binding of CD68-Fc to OxLDL with an affinity of 10 nmol/L was determined by surface plasmon resonance and increased binding to lipid-rich human and ApoE(-/-) mice plaque tissue. This was confirmed both by immunohistochemical staining of CD68-Fc-treated paraffin sections from human plaques and by ELISA-based quantification of CD68-Fc binding to human atherosclerotic plaque extracts. In an in vitro model of macrophage/foam cell formation, CD68-Fc reduced foam cell formation significantly. This was caused both by interference of CD68-Fc with OxLDL uptake into macrophages and platelets and by the inhibition of platelet/OxLDL phagocytosis. Finally, expression of metalloproteinases by macrophages/foam cells was inhibited by CD68-Fc. In conclusion, CD68-Fc seems to be a promising new tool for preventing macrophage/foam cell formation. Thus, CD68-Fc might offer a novel therapeutic strategy for patients with acute coronary syndrome by modulating the generation of vulnerable plaques.
Daub
Karin
K
Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität Tübingen, Otfried-Müller Str.10, 72076 Tübingen, Germany.
Siegel-Axel
Dorothea
D
Schönberger
Tanja
T
Leder
Christoph
C
Seizer
Peter
P
Müller
Karin
K
Schaller
Martin
M
Penz
Sandra
S
Menzel
Dagmar
D
Büchele
Berthold
B
Bültmann
Andreas
A
Münch
Götz
G
Lindemann
Stephan
S
Simmet
Thomas
T
Gawaz
Meinrad
M
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005487:Foam Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014162:Transfection; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D007141:Immunoglobulin Fc Fragments; D008077:Lipoproteins, LDL; D051116:Receptors, Scavenger; D011993:Recombinant Fusion Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C099252:oxidized low density lipoprotein
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