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

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Abstract

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.

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Acknowledgments

We acknowledge the excellent technical assistance of Jadwiga Kwiatkowska, Christina Neff, Birgit Fehrenbacher, and Barbara Proksch. We also thank Maria Lissner and Lydia Kotchoubey of the Dept. of Transfusion Medicine for providing blood samples and Richard Brandl, Vascular Surgery, Krankenhaus München-Schwabing, Germany for providing specimens of carotid atherectomies.

Funding

The study was supported by grants of the Deutsche Forschungsgemeinschaft (Graduiertenkolleg [GK 794] and [GRK 438]) to M.G., K.D. and S.P. and Transregio-SFB-19 “Inflammatorische Kardiomyopathie”) and the Bundesministerium für Bildung und Forschung (BMBF) to D.S., M.G. and C.L.). M.S. was supported by the Deutsche Forschungsgemeinschaft (Sch 897/3, SFB-773 Z2).

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Authors and Affiliations

  1. Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität Tübingen, Otfried-Müller Str.10, 72076, Tübingen, Germany

    Karin Daub, Dorothea Siegel-Axel, Tanja Schönberger, Christoph Leder, Peter Seizer, Karin Müller, Stephan Lindemann & Meinrad Gawaz

  2. Universitäts-Hautklinik, Eberhard-Karls-Universität Tübingen, Tübingen, Germany

    Martin Schaller

  3. Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum Innenstadt, Ludwig-Maximilians-Universität München, München, Germany

    Sandra Penz

  4. Institut für Klinische und Experimentelle Transfusionsmedizin, Eberhard-Karls-Universität Tübingen, Tübingen, Germany

    Dagmar Menzel

  5. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany

    Berthold Büchele & Thomas Simmet

  6. Corimmun, Martinsried, Germany

    Andreas Bültmann & Götz Münch

Authors
  1. Karin Daub
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  2. Dorothea Siegel-Axel
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  3. Tanja Schönberger
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  4. Christoph Leder
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  5. Peter Seizer
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  6. Karin Müller
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  7. Martin Schaller
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  8. Sandra Penz
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  9. Dagmar Menzel
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  10. Berthold Büchele
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  11. Andreas Bültmann
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  12. Götz Münch
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  13. Stephan Lindemann
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  14. Thomas Simmet
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  15. Meinrad Gawaz
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Corresponding author

Correspondence to Meinrad Gawaz.

Additional information

Karin Daub, Dorothea Siegel-Axel, and Tanja Schönberger shared first authorship.

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Daub, K., Siegel-Axel, D., Schönberger, T. et al. Inhibition of foam cell formation using a soluble CD68-Fc fusion protein. J Mol Med 88, 909–920 (2010). https://doi.org/10.1007/s00109-010-0629-y

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  • DOI: https://doi.org/10.1007/s00109-010-0629-y

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