Martin F Reiner1,2,3, Alexander Akhmedov4, Simona Stivala1,3, Stephan Keller2,4, Daniel S Gaul5, Nicole R Bonetti1,2, Gianluigi Savarese6, Martina Glanzmann4, Cuicui Zhu7, Wolfram Ruf8, Zhihong Yang7, Christian M Matter5, Thomas F Lüscher4,9, Giovanni G Camici1,2,9, Juerg H Beer10,3. 1. Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. 2. Laboratory of Aging and Stroke, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. 3. Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland. 4. Laboratory for Endothelial Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. 5. Laboratory for Atherosclerosis Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. 6. Division of Cardiology, Department of Medicine, Karolinska Institute, Solna (MedS), K2, Z5:00, 171 76 Stockholm, Sweden. 7. Department of Medicine/Physiology, University of Fribourg, Chemin du Musée 5, 1700 Fribourg, Switzerland. 8. Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. 9. Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. 10. Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; hansjuerg.beer@ksb.ch.
Abstract
AIMS: The P2Y12 antagonist 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. METHODS AND RESULTS: 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 P2Y12 receptor 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The P2Y12 antagonist 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. METHODS AND RESULTS: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 P2Y12 receptor 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. CONCLUSION: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. Published on behalf of the European Society of Cardiology. All rights reserved.