Inhibition of foam cell formation using a soluble CD68-Fc fusion protein

Autor: Martin Schaller, Karin Müller, Götz Münch, Dagmar Menzel, Thomas Simmet, Tanja Schönberger, Berthold Büchele, Christoph Leder, Dorothea Siegel-Axel, Sandra M Penz, Meinrad Gawaz, Stephan Lindemann, Andreas Bültmann, Karin Daub, Peter Seizer
Rok vydání: 2010
Předmět:
Zdroj: Daub, K, Siegel-Axel, D, Schönberger, T, Leder, C, Seizer, P, Müller, K, Schaller, M, Penz, S, Menzel, D, Buchele, B, Bültmann, A, Münch, G, Lindemann, S, Simmet, T & Gawaz, M 2010, ' Inhibition of foam cell formation using a soluble CD68-Fc fusion protein ', Journal of Molecular Medicine, vol. 88, no. 9, pp. 909-920 . https://doi.org/10.1007/s00109-010-0629-y
Daub, K, Siegel-Axel, D, Schönberger, T, Leder, C, Seizer, P, Müller, K, Schaller, M, Penz, S, Menzel, D, Büchele, B, Bültmann, A, Münch, G, Lindemann, S, Simmet, T & Gawaz, M 2010, ' Inhibition of foam cell formation using a soluble CD68-Fc fusion protein ' Journal of Molecular Medicine, vol 88, no. 9, pp. 909-920 . DOI: 10.1007/s00109-010-0629-y
ISSN: 1432-1440
0946-2716
Popis: 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. 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 surfaceplasmon 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-Fcwith 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/foamcell formation. Thus, CD68-Fc might offer a novel therapeutic strategy for patients with acute coronary syndrome by modulating the generation of vulnerable plaques.
Databáze: OpenAIRE
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