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

Ivo Cornelissen, Daniel Palmer, Tovo David, Lisa Wilsbacher, Cherry Concengco, Pamela Conley, Anjali Pandey, Shaun R. Coughlin

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)18605-18610
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number43
DOIs
StatePublished - Oct 26 2010

Fingerprint

Proteinase-Activated Receptors
Hemostasis
Thrombin
Thrombosis
Blood Platelets
Carotid Artery Thrombosis
clopidogrel
Platelet Activation
Wounds and Injuries
Adenosine Diphosphate
Thrombin Receptors
Purinergic P2 Receptors

Keywords

  • Acute coronary syndromes
  • Myocardial infarction
  • SCH530348
  • Stroke
  • Vorapaxar

ASJC Scopus subject areas

  • General

Cite this

Cornelissen, Ivo ; Palmer, Daniel ; David, Tovo ; Wilsbacher, Lisa ; Concengco, Cherry ; Conley, Pamela ; Pandey, Anjali ; Coughlin, Shaun R. / Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 43. pp. 18605-18610.
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Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. / Cornelissen, Ivo; Palmer, Daniel; David, Tovo; Wilsbacher, Lisa; Concengco, Cherry; Conley, Pamela; Pandey, Anjali; Coughlin, Shaun R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 43, 26.10.2010, p. 18605-18610.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis

AU - Cornelissen, Ivo

AU - Palmer, Daniel

AU - David, Tovo

AU - Wilsbacher, Lisa

AU - Concengco, Cherry

AU - Conley, Pamela

AU - Pandey, Anjali

AU - Coughlin, Shaun R.

PY - 2010/10/26

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AB - 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.

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KW - Stroke

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