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Extracellular cyclophilin A activates platelets via EMMPRIN (CD147) and PI3K/Akt signaling, which promotes platelet adhesion and thrombus formation in vitro and in vivo.
Seizer, Peter; Ungern-Sternberg, Saskia N I V; Schönberger, Tanja; Borst, Oliver; Münzer, Patrick; Schmidt, Eva-Maria; Mack, Andreas F; Heinzmann, David; Chatterjee, Madhumita; Langer, Harald; Malesevic, Miroslav; Lang, Florian; Gawaz, Meinrad; Fischer, Gunter; May, Andreas E.
Afiliação
  • Seizer P; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Ungern-Sternberg SN; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Schönberger T; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Borst O; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Münzer P; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Schmidt EM; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Mack AF; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Heinzmann D; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Chatterjee M; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Langer H; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Malesevic M; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Lang F; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Gawaz M; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • Fischer G; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
  • May AE; From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (P.S., S.N.I.v.U.-S., T.S., O.B., D.H., M.C., H.L., M.G., A.E.M.), Institute of Physiology (P.M., E.-M.S., F.L.), and Institute of Anatomy (A.F.M.), Eberhard Karls-University Tübingen, Tübingen, Germany; Institute of Biochemistr
Arterioscler Thromb Vasc Biol ; 35(3): 655-63, 2015 Mar.
Article em En | MEDLINE | ID: mdl-25550208
OBJECTIVE: Cyclophilin A (CyPA) is secreted under inflammatory conditions by various cell types. Whereas the important role of intracellular CyPA for platelet function has been reported, the effect of extracellular CyPA on platelet function has not been investigated yet. APPROACH AND RESULTS: Inhibition of extracellular CyPA through a novel specific inhibitor MM284 reduced thrombus after ferric chloride-induced injury in vivo. In vitro extracellular CyPA enhanced thrombus formation even in CyPA(-/-) platelets. Treatment of isolated platelets with recombinant CyPA resulted in platelet degranulation in a time- and dose-dependent manner. Inhibition of the platelet surface receptor extracellular matrix metalloproteinase inducer (cluster of differentiation 147) by an anticluster of differentiation 147 monoclonal antibody significantly reduced CyPA-dependent platelet degranulation. Pretreatment of platelets with CyPA enhanced their recruitment to mouse carotid arteries after arterial injury, which could be inhibited by an anticluster of differentiation 147 monoclonal antibody (intravital microscopy). The role of extracellular CyPA in adhesion could be confirmed by infusing CyPA(-/-) platelets in CyPA(+/+) mice and by infusing CyPA(+/+) platelets in CyPA(-/-) mice. Stimulation of platelets with CyPA induced phosphorylation of Akt, which could in turn be inhibited in the presence of phosphoinositid-3-kinase inhibitors. Akt-1(-/-) platelets revealed a markedly decreased degranulation on CyPA stimulation. Finally, ADP-induced platelet aggregation was attenuated by MM284, as well as by inhibiting paracrine-secreted CyPA without directly affecting Ca(2+)-signaling. CONCLUSIONS: Extracellular CyPA activates platelets via cluster of differentiation 147-mediated phosphoinositid-3-kinase/Akt-signaling, leading to enhanced adhesion and thrombus formation independently of intracellular CyPA. Targeting extracellular CyPA via a specific inhibitor may be a promising strategy for platelet inhibition without affecting critical functions of intracellular CyPA.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Plaquetas / Transdução de Sinais / Adesividade Plaquetária / Fosfatidilinositol 3-Quinases / Ciclofilina A / Proteínas Proto-Oncogênicas c-akt / Basigina Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Plaquetas / Transdução de Sinais / Adesividade Plaquetária / Fosfatidilinositol 3-Quinases / Ciclofilina A / Proteínas Proto-Oncogênicas c-akt / Basigina Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article