Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis.

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 FeCl(3) injury. Par4(+/-) and P2ry12(+/-) mice showed partial protection. Increasing FeCl(3) 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.

• Authors: Ivo Cornelissen, Daniel Palmer, Tovo David, Lisa Wilsbacher, Cherry Concengco, Pamela Conley, Anjali Pandey, Shaun R Coughlin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 43 Pg. 18605-10 (Oct 26 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20930120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Adhesion Molecules
• Cell Cycle Proteins
• P2RY12 protein, human
• P2ry12 protein, mouse
• Pard3 protein, mouse
• Receptors, Proteinase-Activated
• Receptors, Purinergic P2Y12
• Receptors, Thrombin
• Adenosine Diphosphate
• Thrombin
• protease-activated receptor 4

Topics

• Adaptor Proteins, Signal Transducing
• Adenosine Diphosphate (blood, pharmacology)
• Animals
• Blood Platelets (drug effects, metabolism)
• Cell Adhesion Molecules (blood, deficiency, genetics)
• Cell Cycle Proteins
• Female
• Hemostasis (physiology)
• Humans
• In Vitro Techniques
• Male
• Mice
• Mice, Knockout
• Models, Biological
• Receptors, Proteinase-Activated (blood, deficiency, genetics)
• Receptors, Purinergic P2Y12 (blood, deficiency, genetics)
• Receptors, Thrombin (blood, deficiency, genetics)
• Signal Transduction
• Thrombin (metabolism, pharmacology)
• Thrombosis (blood, etiology)