Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.

<h4>Background and objectives</h4>Thrombomodulin (TM), an integral membrane glycoprotein expressed on the lumenal surface of vascular endothelial cells, promotes anti-coagulant and anti-inflammatory properties. Release of functional TM from the endothelium surface into plasma has also be...

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Autores principales:	Fiona A Martin, Alisha McLoughlin, Keith D Rochfort, Colin Davenport, Ronan P Murphy, Philip M Cummins
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4dbe4fdfd97347e0bfe9271804d3ed15
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spelling	oai:doaj.org-article:4dbe4fdfd97347e0bfe9271804d3ed152021-11-25T06:00:00ZRegulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.1932-620310.1371/journal.pone.0108254https://doaj.org/article/4dbe4fdfd97347e0bfe9271804d3ed152014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0108254https://doaj.org/toc/1932-6203<h4>Background and objectives</h4>Thrombomodulin (TM), an integral membrane glycoprotein expressed on the lumenal surface of vascular endothelial cells, promotes anti-coagulant and anti-inflammatory properties. Release of functional TM from the endothelium surface into plasma has also been reported. Much is still unknown however about how endothelial TM is regulated by physiologic hemodynamic forces (and particularly cyclic strain) intrinsic to endothelial-mediated vascular homeostasis.<h4>Methods</h4>This study employed human aortic endothelial cells (HAECs) to investigate the effects of equibiaxial cyclic strain (7.5%, 60 cycles/min, 24 hrs), and to a lesser extent, laminar shear stress (10 dynes/cm2, 24 hrs), on TM expression and release. Time-, dose- and frequency-dependency studies were performed.<h4>Results</h4>Our initial studies demonstrated that cyclic strain strongly downregulated TM expression in a p38- and receptor tyrosine kinase-dependent manner. This was in contrast to the upregulatory effect of shear stress. Moreover, both forces significantly upregulated TM release over a 48 hr period. With continuing focus on the cyclic strain-induced TM release, we noted both dose (0-7.5%) and frequency (0.5-2.0 Hz) dependency, with no attenuation of strain-induced TM release observed following inhibition of MAP kinases (p38, ERK-1/2), receptor tyrosine kinase, or eNOS. The concerted impact of cyclic strain and inflammatory mediators on TM release from HAECs was also investigated. In this respect, both TNFα (100 ng/ml) and ox-LDL (10-50 µg/ml) appeared to potentiate strain-induced TM release. Finally, inhibition of neither MMPs (GM6001) nor rhomboids (3,4-dichloroisocoumarin) had any effect on strain-induced TM release. However, significantly elevated levels (2.1 fold) of TM were observed in isolated microparticle fractions following 7.5% strain for 24 hrs.<h4>Conclusions</h4>A preliminary in vitro investigation into the effects of cyclic strain on TM in HAECs is presented. Physiologic cyclic strain was observed to downregulate TM expression, whilst upregulating in a time-, dose- and frequency-dependent manner the release of TM.Fiona A MartinAlisha McLoughlinKeith D RochfortColin DavenportRonan P MurphyPhilip M CumminsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e108254 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fiona A Martin Alisha McLoughlin Keith D Rochfort Colin Davenport Ronan P Murphy Philip M Cummins Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
description	<h4>Background and objectives</h4>Thrombomodulin (TM), an integral membrane glycoprotein expressed on the lumenal surface of vascular endothelial cells, promotes anti-coagulant and anti-inflammatory properties. Release of functional TM from the endothelium surface into plasma has also been reported. Much is still unknown however about how endothelial TM is regulated by physiologic hemodynamic forces (and particularly cyclic strain) intrinsic to endothelial-mediated vascular homeostasis.<h4>Methods</h4>This study employed human aortic endothelial cells (HAECs) to investigate the effects of equibiaxial cyclic strain (7.5%, 60 cycles/min, 24 hrs), and to a lesser extent, laminar shear stress (10 dynes/cm2, 24 hrs), on TM expression and release. Time-, dose- and frequency-dependency studies were performed.<h4>Results</h4>Our initial studies demonstrated that cyclic strain strongly downregulated TM expression in a p38- and receptor tyrosine kinase-dependent manner. This was in contrast to the upregulatory effect of shear stress. Moreover, both forces significantly upregulated TM release over a 48 hr period. With continuing focus on the cyclic strain-induced TM release, we noted both dose (0-7.5%) and frequency (0.5-2.0 Hz) dependency, with no attenuation of strain-induced TM release observed following inhibition of MAP kinases (p38, ERK-1/2), receptor tyrosine kinase, or eNOS. The concerted impact of cyclic strain and inflammatory mediators on TM release from HAECs was also investigated. In this respect, both TNFα (100 ng/ml) and ox-LDL (10-50 µg/ml) appeared to potentiate strain-induced TM release. Finally, inhibition of neither MMPs (GM6001) nor rhomboids (3,4-dichloroisocoumarin) had any effect on strain-induced TM release. However, significantly elevated levels (2.1 fold) of TM were observed in isolated microparticle fractions following 7.5% strain for 24 hrs.<h4>Conclusions</h4>A preliminary in vitro investigation into the effects of cyclic strain on TM in HAECs is presented. Physiologic cyclic strain was observed to downregulate TM expression, whilst upregulating in a time-, dose- and frequency-dependent manner the release of TM.
format	article
author	Fiona A Martin Alisha McLoughlin Keith D Rochfort Colin Davenport Ronan P Murphy Philip M Cummins
author_facet	Fiona A Martin Alisha McLoughlin Keith D Rochfort Colin Davenport Ronan P Murphy Philip M Cummins
author_sort	Fiona A Martin
title	Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
title_short	Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
title_full	Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
title_fullStr	Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
title_full_unstemmed	Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
title_sort	regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/4dbe4fdfd97347e0bfe9271804d3ed15
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Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.

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