Inhibition of foam cell formation using a soluble CD68-Fc fusion protein
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In: Journal of Molecular Medicine, Vol. 88, No. 9, 09.2010, p. 909-920.
Research output: Journal contributions › Journal articles › Research › peer-review
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TY - JOUR
T1 - Inhibition of foam cell formation using a soluble CD68-Fc fusion protein
AU - Daub, Karin
AU - Siegel-Axel, Dorothea
AU - Schönberger, Tanja
AU - Leder, Christoph
AU - Seizer, Peter
AU - Müller, Karin
AU - Schaller, Martin
AU - Penz, Susanne
AU - Menzel, Dirk
AU - Buchele, Berthold
AU - Bültmann, Andreas
AU - Münch, Götz
AU - Lindemann, Stephan
AU - Simmet, Thomas
AU - Gawaz, Meinrad
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
KW - Chemistry
KW - Atherosclerosis
KW - Foam cells
KW - Lipoproteins
KW - Macrophages
KW - Platelets
UR - http://www.scopus.com/inward/record.url?scp=77956420059&partnerID=8YFLogxK
U2 - 10.1007/s00109-010-0629-y
DO - 10.1007/s00109-010-0629-y
M3 - Journal articles
C2 - 20454888
VL - 88
SP - 909
EP - 920
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 9
ER -