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The Role of P2Y12 Receptor Antagonists in Thrombogenesis

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The Role of P2Y12 Receptor Antagonists in Thrombogenesis Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 The Role of P2Y12 Receptor Antagonists in Thrombogenesis Reiner, Martin F Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148533 Dissertation Published Version Originally published at: Reiner, Martin F. The Role of P2Y12 Receptor Antagonists in Thrombogenesis. 2017, University of Zurich, Faculty of Science. The Role of P2Y12 Receptor Antagonists in Thrombogenesis Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Martin Reiner aus Österreich Promotionskommission Prof. Dr. Olivier Devuyst (Vorsitz) Prof. Dr. Giovanni Guido Camici (Leitung der Dissertation) Prof. Dr. Carsten Wagner Prof. Dr. Thomas Felix Lüscher Prof. Dr. Jürg-Hans Beer Zürich, 2017 Acknowledgments First, I would like to thank my supervisor Prof. Dr. Giovanni G. Camici, who has introduced me to basic research, taught me numerous technical and manual skills and how to work with utmost accuracy. The close personal supervision I received over years has played a decisive role for my progress in basic research. Lastly, I am thankful for the motivation he gave me, if results diverged from my expectations and for successful trouble-shooting and apart from that, for some great time outside the laboratory. Next, I would like to thank Prof. Dr. med. Jürg-Hans Beer, who provided me close supervision during my basic research career and beyond. I am grateful for his countless ideas, and hypothesis that resulted in many projects and collaborations. I was inspired by his expertise and commitment to science, which motivated and encouraged me in many ways. Besides, I am glad for all the support I received whenever needed. Also, I am grateful to Prof. Dr. med. Thomas F. Lüscher, who has given me the chance to work in the laboratory and to be part of the team; who has contributed with his critical statements and with his endless knowledge to the successful outcomes of our projects. Further, I am thankful to Prof. Dr. med. Paul M. Vanhoutte who has influenced the direction of some projects with his critical and constructive remarks in regular meetings. Lastly, I would like to thank all members of the Center for Molecular Cardiology for numerous scientific exchanges and support concerning my experimental procedures and interpretations. 2 Table of contents 1 Zusammenfassung .......................................................................................................... 5 1.1 Hintergrund ................................................................................................................ 5 1.2 Material und Methoden ............................................................................................. 5 1.3 Ergebnisse ................................................................................................................. 6 1.4 Konklusionen ............................................................................................................. 6 2 Summary ........................................................................................................................... 7 2.1 Background ................................................................................................................ 7 2.2 Material and methods ............................................................................................... 7 2.3 Results ........................................................................................................................ 8 2.4 Conclusions ............................................................................................................... 8 3 Introduction ...................................................................................................................... 9 3.1 Epidemiology of cardiovascular disease ................................................................ 9 3.2 Endothelial function and dysfunction ................................................................... 10 Vessel wall ...................................................................................................................... 10 Endothelial function ......................................................................................................... 10 Endothelial dysfunction and reactive oxygen species ..................................................... 11 3.3 Atherosclerosis ....................................................................................................... 12 3.4 Tissue factor and initiation of the coagulation cascade ..................................... 14 Tissue factor ................................................................................................................... 14 Initiation of the coagulation cascade ............................................................................... 16 Experimental and clinical studies .................................................................................... 17 3.5 Platelets and the P2Y12 receptor ............................................................................ 17 Platelets .......................................................................................................................... 17 Adenosine diphosphate and the P2Y receptors .............................................................. 19 3.6 P2Y12 receptor antagonists .................................................................................... 20 The thienopyridines clopidogrel and prasugrel ............................................................... 21 The cyclopentyl-triazolo-pyrimidine ticagrelor ................................................................. 21 Pleiotropic effects of P2Y12 receptor antagonists ............................................................ 22 3.7 Atherothrombosis ................................................................................................... 23 Atherosclerotic plaques ................................................................................................... 23 Platelet adhesion, activation and recruitment ................................................................. 24 Initiation, amplification and propagation of the coagulation cascade .............................. 25 3.8 State of research in the field .................................................................................. 25 3 4 References ..................................................................................................................... 27 5 Original Articles ............................................................................................................. 45 6 Summary ......................................................................................................................... 93 6.1 Ticagrelor, but not clopidogrel active metabolite, reduces endothelial tissue factor via proteasomal degradation ............................................................................... 93 6.2 Ticagrelor, compared with clopidogrel, decreases endothelial tissue factor expression and arterial thrombosis in mice .................................................................. 94 6.3 Ticagrelor, unlike clopidogrel active metabolite, reduces thrombogenicity in atrial fibrillation patients .................................................................................................. 94 7 Discussion ...................................................................................................................... 96 7.1 Ticagrelor exhibits platelet-independent antithrombotic effects on the endothelium ...................................................................................................................... 96 7.2 Ticagrelor-mediated tissue factor reduction in endothelial cells and its underlying molecular mechanisms ................................................................................ 97 7.3 Ticagrelor and arterial thrombosis in vivo – relevance of endothelial tissue factor .................................................................................................................................. 99 Drug dosages of P2Y12 receptor antagonists in rodents ............................................. 101 8 Outlook ......................................................................................................................... 102 9 Abbreviations ............................................................................................................... 105 10 References ................................................................................................................. 107 11 Declaration of personal contributions to work ....................................................... 114 11.1 Ticagrelor, but not Clopidogrel, Reduces Arterial Thrombosis via Endothelial Tissue Factor Suppression ........................................................................................... 114 11.2 Ticagrelor, but not Clopidogrel Active Metabolite, Displays Antithrombotic Properties in the Left Atrial Endocardium ................................................................... 115 12 Curriculum Vitae ........................................................................................................ 116 4 1 Zusammenfassung 1.1 Hintergrund Der Adenosindiphosphat-Rezeptor P2Y12 bewirkt Plättchenaggregation
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