Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice

Autores
Devanathan, Vasudharani; Hagedorn, Ina; Köhler, David; Pexa, Katja; Cherpokova, Deya; Kraft, Peter; Singh, Madhurendra; Rosenberger, Peter; Stoll, Guido; Birnbaumer, Lutz; Piekorz, Roland P.; Beer-Hammer, Sandra; Nieswandt, Bernhard; Nürnberg, Bernd
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The Gi protein Gα(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα(i2) in megakaryocytes and platelets (Gna(i2)(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global Gα(i2)-deficient mice. To examine the impact of platelet Gα(i2) in postischemic thrombo-inflammatory infarct progression, Gna(i2)(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gna(i2)(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gna(i2)(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo.
Fil: Devanathan, Vasudharani. University of Tübingen; Alemania
Fil: Hagedorn, Ina. University Hospital; Alemania
Fil: Köhler, David. University of Tübingen; Alemania
Fil: Pexa, Katja. Universitat Dusseldorf; Alemania
Fil: Cherpokova, Deya. University Hospital; Alemania
Fil: Kraft, Peter. Universität Würzburg; Alemania
Fil: Singh, Madhurendra. Universitat Dusseldorf; Alemania
Fil: Rosenberger, Peter. University of Tübingen; Alemania
Fil: Stoll, Guido. Universität Würzburg; Alemania
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Research Triangle Park; Alemania
Fil: Piekorz, Roland P.. Universitat Dusseldorf; Alemania
Fil: Beer-Hammer, Sandra. University of Tübingen; Alemania
Fil: Nieswandt, Bernhard. University Hospital; Alemania
Fil: Nürnberg, Bernd. University of Tübingen; Alemania
Materia
G proteins
Platelets
Ischemia reperfusion injury
P2Y12 receptor
Thrombosis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/43529
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/43529
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in miceDevanathan, VasudharaniHagedorn, InaKöhler, DavidPexa, KatjaCherpokova, DeyaKraft, PeterSingh, MadhurendraRosenberger, PeterStoll, GuidoBirnbaumer, LutzPiekorz, Roland P.Beer-Hammer, SandraNieswandt, BernhardNürnberg, BerndG proteinsPlateletsIschemia reperfusion injuryP2Y12 receptorThrombosishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The Gi protein Gα(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα(i2) in megakaryocytes and platelets (Gna(i2)(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global Gα(i2)-deficient mice. To examine the impact of platelet Gα(i2) in postischemic thrombo-inflammatory infarct progression, Gna(i2)(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gna(i2)(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gna(i2)(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo.Fil: Devanathan, Vasudharani. University of Tübingen; AlemaniaFil: Hagedorn, Ina. University Hospital; AlemaniaFil: Köhler, David. University of Tübingen; AlemaniaFil: Pexa, Katja. Universitat Dusseldorf; AlemaniaFil: Cherpokova, Deya. University Hospital; AlemaniaFil: Kraft, Peter. Universität Würzburg; AlemaniaFil: Singh, Madhurendra. Universitat Dusseldorf; AlemaniaFil: Rosenberger, Peter. University of Tübingen; AlemaniaFil: Stoll, Guido. Universität Würzburg; AlemaniaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Research Triangle Park; AlemaniaFil: Piekorz, Roland P.. Universitat Dusseldorf; AlemaniaFil: Beer-Hammer, Sandra. University of Tübingen; AlemaniaFil: Nieswandt, Bernhard. University Hospital; AlemaniaFil: Nürnberg, Bernd. University of Tübingen; AlemaniaNational Academy of Sciences2015-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/43529Devanathan, Vasudharani; Hagedorn, Ina; Köhler, David; Pexa, Katja; Cherpokova, Deya; et al.; Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 112; 20; 5-2015; 6491-64960027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1505887112info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/112/20/6491info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:04:58Zoai:ri.conicet.gov.ar:11336/43529instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:04:58.685CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
title Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
spellingShingle Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
Devanathan, Vasudharani
G proteins
Platelets
Ischemia reperfusion injury
P2Y12 receptor
Thrombosis
title_short Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
title_full Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
title_fullStr Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
title_full_unstemmed Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
title_sort Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
dc.creator.none.fl_str_mv Devanathan, Vasudharani
Hagedorn, Ina
Köhler, David
Pexa, Katja
Cherpokova, Deya
Kraft, Peter
Singh, Madhurendra
Rosenberger, Peter
Stoll, Guido
Birnbaumer, Lutz
Piekorz, Roland P.
Beer-Hammer, Sandra
Nieswandt, Bernhard
Nürnberg, Bernd
author Devanathan, Vasudharani
author_facet Devanathan, Vasudharani
Hagedorn, Ina
Köhler, David
Pexa, Katja
Cherpokova, Deya
Kraft, Peter
Singh, Madhurendra
Rosenberger, Peter
Stoll, Guido
Birnbaumer, Lutz
Piekorz, Roland P.
Beer-Hammer, Sandra
Nieswandt, Bernhard
Nürnberg, Bernd
author_role author
author2 Hagedorn, Ina
Köhler, David
Pexa, Katja
Cherpokova, Deya
Kraft, Peter
Singh, Madhurendra
Rosenberger, Peter
Stoll, Guido
Birnbaumer, Lutz
Piekorz, Roland P.
Beer-Hammer, Sandra
Nieswandt, Bernhard
Nürnberg, Bernd
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv G proteins
Platelets
Ischemia reperfusion injury
P2Y12 receptor
Thrombosis
topic G proteins
Platelets
Ischemia reperfusion injury
P2Y12 receptor
Thrombosis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The Gi protein Gα(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα(i2) in megakaryocytes and platelets (Gna(i2)(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global Gα(i2)-deficient mice. To examine the impact of platelet Gα(i2) in postischemic thrombo-inflammatory infarct progression, Gna(i2)(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gna(i2)(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gna(i2)(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo.
Fil: Devanathan, Vasudharani. University of Tübingen; Alemania
Fil: Hagedorn, Ina. University Hospital; Alemania
Fil: Köhler, David. University of Tübingen; Alemania
Fil: Pexa, Katja. Universitat Dusseldorf; Alemania
Fil: Cherpokova, Deya. University Hospital; Alemania
Fil: Kraft, Peter. Universität Würzburg; Alemania
Fil: Singh, Madhurendra. Universitat Dusseldorf; Alemania
Fil: Rosenberger, Peter. University of Tübingen; Alemania
Fil: Stoll, Guido. Universität Würzburg; Alemania
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Research Triangle Park; Alemania
Fil: Piekorz, Roland P.. Universitat Dusseldorf; Alemania
Fil: Beer-Hammer, Sandra. University of Tübingen; Alemania
Fil: Nieswandt, Bernhard. University Hospital; Alemania
Fil: Nürnberg, Bernd. University of Tübingen; Alemania
description Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The Gi protein Gα(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα(i2) in megakaryocytes and platelets (Gna(i2)(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global Gα(i2)-deficient mice. To examine the impact of platelet Gα(i2) in postischemic thrombo-inflammatory infarct progression, Gna(i2)(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gna(i2)(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gna(i2)(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo.
publishDate 2015
dc.date.none.fl_str_mv 2015-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/43529
Devanathan, Vasudharani; Hagedorn, Ina; Köhler, David; Pexa, Katja; Cherpokova, Deya; et al.; Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 112; 20; 5-2015; 6491-6496
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/43529
identifier_str_mv Devanathan, Vasudharani; Hagedorn, Ina; Köhler, David; Pexa, Katja; Cherpokova, Deya; et al.; Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 112; 20; 5-2015; 6491-6496
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1505887112
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/112/20/6491
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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