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Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata

Brokopp, Chad E. ; Schoenauer, Roman ; Richards, Peter ; Bauer, Stefan ; Lohmann, Christine ; Emmert, Maximilian Y. ; Weber, Benedikt ; Winnik, Stephan ; Aikawa, Elena ; Graves, Kirk ; Genoni, Michele ; Vogt, Peter ; Lüscher, Thomas F. ; Renner, Christoph ; Hoerstrup, Simon P. ; Matter, Christian M.

In: European Heart Journal, 2011, vol. 32, no. 21, p. 2713-2722

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    Titel
    • Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata
    Autor
    • Brokopp, Chad E.. Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Schoenauer, Roman. Swiss Center for Regenerative Medicine, University Hospital Zurich, Zurich, Switzerland
    • Richards, Peter. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    • Bauer, Stefan. Oncology, National Center for Tumor Diseases, Heidelberg, Germany
    • Lohmann, Christine. Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Emmert, Maximilian Y.. Swiss Center for Regenerative Medicine, University Hospital Zurich, Zurich, Switzerland
    • Weber, Benedikt. Swiss Center for Regenerative Medicine, University Hospital Zurich, Zurich, Switzerland
    • Winnik, Stephan. Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Aikawa, Elena. Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    • Graves, Kirk. Cardiovascular Surgery, Triemli Hospital Zurich, Zurich, Switzerland
    • Genoni, Michele. Cardiovascular Surgery, Triemli Hospital Zurich, Zurich, Switzerland
    • Vogt, Peter. Department of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
    • Lüscher, Thomas F.. Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Renner, Christoph. Oncology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
    • Hoerstrup, Simon P.. Swiss Center for Regenerative Medicine, University Hospital Zurich, Zurich, Switzerland
    • Matter, Christian M.. Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • European Heart Journal, 2011, vol. 32, no. 21, p. 2713-2722. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:293433
    Summary
    Aims Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown. Methods and results We detected enhanced FAP expression in type IV-V human aortic atheromata (n = 12), compared with type II-III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 µm) vs. thick-cap (≥65 µm) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R2= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor α (TNFα) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFα (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01). Conclusion Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFα. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous caps