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Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo

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Abstract

Platelet adhesion to the atherosclerotic vascular wall induces thrombosis and boosters vascular inflammation and atheroprogression. In the present study we studied the binding of the platelet collagen receptor glycoprotein (GP) VI to human atherosclerotic plaques (AP) and the role of GPVI-mediated platelet adhesion for atheroprogression. Soluble GPVI-Fc fusion protein bound to immobilized collagen type I, collagen type III, and predominantly to the core region of human carotid atheromatous plaques. The pattern of GPVI-Fc binding was similar to the immunostaining pattern of collagen type III and differed from the immunostaining of collagen type I, which was more intense in the cap than in the core. Plaque-induced platelet aggregation in stirred blood and platelet adhesion/aggregate formation under flow were inhibited by the anti-GPVI monoclonal antibody 5C4 or by pretreatment of plaques with anti-collagen type I and anti-collagen type III antibody, or GPVI-Fc. However, there was no correlation between GPVI-Fc binding and platelet aggregating activity of individual plaques. GPVI bound also to atherosclerotic arteries of ApoE-deficient mice in vivo as assessed by small animal positron emission tomography (PET). Prolonged administration of soluble GPVI attenuated atheroprogression in ApoE-deficient mice. In humans, GPVI binding to collagenous type I and type III structures of the plaque core region mediates plaque-induced platelet adhesion and aggregation, but GPVI binding is not the sole platelet-activating determinant of plaques. In mice, GPVI-mediated platelet adhesion to the atherosclerotic vascular wall is involved in atheroprogression in vivo. Taken together, our data suggests that GPVI is a relevant target to prevent atherothrombotic events and atheroprogression.

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Acknowledgments

We acknowledge the excellent technical assistance of Heike Runge, Renate Hegenloh, Sandra Kerstan and Kirsten Langenbrink. The study was supported by grants of the Deutsche Forschungsgemeinschaft (Si 274/9), the DFG-graduate programs “Zellbiologische Mechanismen immunassoziierter Prozesse” (GK 794) and “Vaskuläre Biologie in der Medizin” (GK 438) to S.P. and K.D., and grants of the Deutsche Forschungsgemeinschaft (MA 2186/3-1) and Wilhelm-Vaillant-Stiftung to C.S.

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Authors and Affiliations

  1. Deutsches Herzzentrum und 1. Medizinische Klinik Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Christian Schulz, Christof Hoffmann, Simon Schneider & Steffen Massberg

  2. Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Universität München, Munich, Germany

    Sandra Penz & Wolfgang Siess

  3. Medizinische Klinik III, Eberhard-Karls Universität, 72076, Tübingen, Germany

    Harald Langer, Angelika Gillitzer, Konstantinos Stellos, Tanja Schönberger & Meinrad Gawaz MD

  4. Abteilung für Gefäßchirurgie Klinikum München-Schwabing, Munich, Germany

    Richard Brandl

  5. Institut für Pathologie Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Stefan Seidl

  6. Radiologische Klinik, Eberhard-Karls Universität, Munich, Germany

    Bernd Pichler

  7. Institut für Molekulare Immunologie, GSF - Forschungszentrum für Umwelt und Gesundheit, Munich, Germany

    Elisabeth Kremmer

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  1. Christian Schulz
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  2. Sandra Penz
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  3. Christof Hoffmann
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  7. Richard Brandl
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  15. Meinrad Gawaz MD
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Corresponding author

Correspondence to Meinrad Gawaz MD.

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Returned for 1. Revision: 8 February 2008 1. Revision received: 18 February 2008

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Schulz, C., Penz, S., Hoffmann, C. et al. Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo. Basic Res Cardiol 103, 356–367 (2008). https://doi.org/10.1007/s00395-008-0722-3

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  • DOI: https://doi.org/10.1007/s00395-008-0722-3

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