Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis
- 7 October 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (43), 18605-18610
- https://doi.org/10.1073/pnas.1013309107
Abstract
Toward understanding their redundancies and interactions in hemostasis and thrombosis, we examined the roles of thrombin receptors (protease-activated receptors, PARs) and the ADP receptor P2RY12 (purinergic receptor P2Y G protein-coupled 12) in human and mouse platelets ex vivo and in mouse models. Par3−/− and Par4+/− mouse platelets showed partially decreased responses to thrombin, resembling those in PAR1 antagonist-treated human platelets. P2ry12+/− mouse platelets showed partially decreased responses to ADP, resembling those in clopidogrel-treated human platelets. Par3−/− mice showed nearly complete protection against carotid artery thrombosis caused by low FeCl3 injury. Par4+/− and P2ry12+/− mice showed partial protection. Increasing FeCl3 injury abolished such protection; combining partial attenuation of thrombin and ADP signaling, as in Par3−/−:P2ry12+/− mice, restored it. Par4−/− mice, which lack platelet thrombin responses, showed still better protection. Our data suggest that (i) the level of thrombin driving platelet activation and carotid thrombosis was low at low levels of arterial injury and increased along with the contribution of thrombin-independent pathways of platelet activation with increasing levels of injury; (ii) although P2ry12 acts downstream of PARs to amplify platelet responses to thrombin ex vivo, P2ry12 functioned in thrombin/PAR-independent pathways in our in vivo models; and (iii) P2ry12 signaling was more important than PAR signaling in hemostasis models; the converse was noted for arterial thrombosis models. These results make predictions being tested by ongoing human trials and suggest hypotheses for new antithrombotic strategies.Keywords
This publication has 26 references indexed in Scilit:
- Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind studyThe Lancet, 2010
- The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER) trial: study design and rationaleAmerican Heart Journal, 2009
- Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: Design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trialAmerican Heart Journal, 2009
- Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet ActivityJournal of Medicinal Chemistry, 2008
- Prasugrel versus Clopidogrel in Patients with Acute Coronary SyndromesNew England Journal of Medicine, 2007
- Anticoagulants (Thrombin Inhibitors) and Aspirin Synergize With P2Y 12 Receptor Antagonism in ThrombosisCirculation, 2003
- Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activationCell, 1991
- PADGEM protein: A receptor that mediates the interaction of activated platelets with neutrophils and monocytesCell, 1989
- Interrelations of Platelet Aggregation and SecretionJCI Insight, 1977
- Actions of Thrombin and Other Coagulant and Proteolytic Enzymes on Blood PlateletsNature, 1967