Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression

Abstract Epac1 (Exchange protein directly activated by cAMP 1) limits fluid loss from the circulation by tightening the endothelial barrier. We show here that Epac1−/− mice, but not Epac2−/− mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding....

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Autores principales:	Gyrid Nygaard, Lars Herfindal, Kathrine S. Asrud, Ronja Bjørnstad, Reidun K. Kopperud, Eystein Oveland, Frode S. Berven, Lene Myhren, Erling A. Hoivik, Turid Helen Felli Lunde, Marit Bakke, Stein O. Døskeland, Frode Selheim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f75be00c06b64f34bcf497f723b222ec
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spelling	oai:doaj.org-article:f75be00c06b64f34bcf497f723b222ec2021-12-02T16:06:33ZEpac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression10.1038/s41598-017-08975-y2045-2322https://doaj.org/article/f75be00c06b64f34bcf497f723b222ec2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08975-yhttps://doaj.org/toc/2045-2322Abstract Epac1 (Exchange protein directly activated by cAMP 1) limits fluid loss from the circulation by tightening the endothelial barrier. We show here that Epac1−/− mice, but not Epac2−/− mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding. The Epac1−/− mice had deficient in vitro secondary hemostasis. Quantitative comprehensive proteomics analysis revealed that Epac1−/− mouse platelets (thrombocytes) had unbalanced expression of key components of the glycoprotein Ib-IX-V (GPIb-IX-V) complex, with decrease of GP1bβ and no change of GP1bα. This complex is critical for platelet adhesion under arterial shear conditions. Furthermore, Epac1−/− mice have reduced levels of plasma coagulation factors and fibrinogen, increased size of circulating platelets, increased megakaryocytes (the GP1bβ level was decreased also in Epac1−/− bone marrow) and higher abundance of reticulated platelets. Viscoelastic measurement of clotting function revealed Epac1−/− mice with a dysfunction in the clotting process, which corresponds to reduced plasma levels of coagulation factors like factor XIII and fibrinogen. We propose that the observed platelet phenotype is due to deficient Epac1 activity during megakaryopoiesis and thrombopoiesis, and that the defects in blood clotting for Epac1−/− is connected to secondary hemostasis.Gyrid NygaardLars HerfindalKathrine S. AsrudRonja BjørnstadReidun K. KopperudEystein OvelandFrode S. BervenLene MyhrenErling A. HoivikTurid Helen Felli LundeMarit BakkeStein O. DøskelandFrode SelheimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gyrid Nygaard Lars Herfindal Kathrine S. Asrud Ronja Bjørnstad Reidun K. Kopperud Eystein Oveland Frode S. Berven Lene Myhren Erling A. Hoivik Turid Helen Felli Lunde Marit Bakke Stein O. Døskeland Frode Selheim Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression
description	Abstract Epac1 (Exchange protein directly activated by cAMP 1) limits fluid loss from the circulation by tightening the endothelial barrier. We show here that Epac1−/− mice, but not Epac2−/− mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding. The Epac1−/− mice had deficient in vitro secondary hemostasis. Quantitative comprehensive proteomics analysis revealed that Epac1−/− mouse platelets (thrombocytes) had unbalanced expression of key components of the glycoprotein Ib-IX-V (GPIb-IX-V) complex, with decrease of GP1bβ and no change of GP1bα. This complex is critical for platelet adhesion under arterial shear conditions. Furthermore, Epac1−/− mice have reduced levels of plasma coagulation factors and fibrinogen, increased size of circulating platelets, increased megakaryocytes (the GP1bβ level was decreased also in Epac1−/− bone marrow) and higher abundance of reticulated platelets. Viscoelastic measurement of clotting function revealed Epac1−/− mice with a dysfunction in the clotting process, which corresponds to reduced plasma levels of coagulation factors like factor XIII and fibrinogen. We propose that the observed platelet phenotype is due to deficient Epac1 activity during megakaryopoiesis and thrombopoiesis, and that the defects in blood clotting for Epac1−/− is connected to secondary hemostasis.
format	article
author	Gyrid Nygaard Lars Herfindal Kathrine S. Asrud Ronja Bjørnstad Reidun K. Kopperud Eystein Oveland Frode S. Berven Lene Myhren Erling A. Hoivik Turid Helen Felli Lunde Marit Bakke Stein O. Døskeland Frode Selheim
author_facet	Gyrid Nygaard Lars Herfindal Kathrine S. Asrud Ronja Bjørnstad Reidun K. Kopperud Eystein Oveland Frode S. Berven Lene Myhren Erling A. Hoivik Turid Helen Felli Lunde Marit Bakke Stein O. Døskeland Frode Selheim
author_sort	Gyrid Nygaard
title	Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression
title_short	Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression
title_full	Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression
title_fullStr	Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression
title_full_unstemmed	Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression
title_sort	epac1-deficient mice have bleeding phenotype and thrombocytes with decreased gpibβ expression
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f75be00c06b64f34bcf497f723b222ec
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Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression

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