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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Main Authors:	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
Format:	Article
Language:	English
Published:	Nature Publishing Group 2017-08-01
Series:	Scientific Reports
Online Access:	https://doi.org/10.1038/s41598-017-08975-y

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spelling	doaj-f75be00c06b64f34bcf497f723b222ec2020-12-08T01:02:27ZengNature Publishing GroupScientific Reports2045-23222017-08-017111510.1038/s41598-017-08975-yEpac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expressionGyrid Nygaard0Lars Herfindal1Kathrine S. Asrud2Ronja Bjørnstad3Reidun K. Kopperud4Eystein Oveland5Frode S. Berven6Lene Myhren7Erling A. Hoivik8Turid Helen Felli Lunde9Marit Bakke10Stein O. Døskeland11Frode Selheim12Department of Biomedicine, University of BergenCentre for Pharmacy, Department of Clinical Science, University of BergenDepartment of Biomedicine, University of BergenCentre for Pharmacy, Department of Clinical Science, University of BergenDepartment of Biomedicine, University of BergenThe Proteomics Unit at the University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Clinical Science, University of BergenDepartment of Immunology and Transfusion Medicine, Haukeland University HospitalDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenAbstract 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.https://doi.org/10.1038/s41598-017-08975-y
collection	DOAJ
language	English
format	Article
sources	DOAJ
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
spellingShingle	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 Scientific Reports
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 Publishing Group
series	Scientific Reports
issn	2045-2322
publishDate	2017-08-01
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.
url	https://doi.org/10.1038/s41598-017-08975-y
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Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression

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