title: Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression.
abstract: The P2Y12antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.
  
  
  
  Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-α-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries.
  
  
  
  Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor.
authors.affiliation: Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Laboratory of Aging and Stroke, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Reiner
authors.affiliation: Laboratory for Endothelial Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.affiliation: Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Stivala
authors.affiliation: Laboratory of Aging and Stroke, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Laboratory for Endothelial Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Keller
authors.affiliation: Laboratory for Atherosclerosis Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Gaul
authors.affiliation: Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Laboratory of Aging and Stroke, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Bonetti
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institute, Solna (MedS), K2, Z5:00, 171 76 Stockholm, Sweden.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Savarese
authors.affiliation: Laboratory for Endothelial Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Glanzmann
authors.affiliation: Department of Medicine/Physiology, University of Fribourg, Chemin du Musée 5, 1700 Fribourg, Switzerland.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.affiliation: Department of Medicine/Physiology, University of Fribourg, Chemin du Musée 5, 1700 Fribourg, Switzerland.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Laboratory for Atherosclerosis Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.affiliation: Laboratory for Endothelial Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Laboratory of Aging and Stroke, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; hansjuerg.beer@ksb.ch.|Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland.
authors.forename: Juerg H
authors.initials: JH
authors.lastname: Beer
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D002478:Cells, Cultured; D000077144:Clopidogrel; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D033721:Equilibrative Nucleoside Transporter 1 / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D005343:Fibrinolytic Agents; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; C438649:SLC29A1 protein, human; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin; D000077144:Clopidogrel; D046988:Proteasome Endopeptidase Complex; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: Clopidogrel; Coagulation; Endothelium; Thrombosis; Ticagrelor; Tissue factor