Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability

Abstract Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulatio...

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Autores principales:	M. Z. Yusuf, Z. Raslan, L. Atkinson, A. Aburima, S. G. Thomas, K. M. Naseem, S. D. J. Calaminus
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/59e911bd8ed54800bd16bc7e224dceb4
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spelling	oai:doaj.org-article:59e911bd8ed54800bd16bc7e224dceb42021-12-02T16:07:57ZProstacyclin reverses platelet stress fibre formation causing platelet aggregate instability10.1038/s41598-017-05817-92045-2322https://doaj.org/article/59e911bd8ed54800bd16bc7e224dceb42017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05817-9https://doaj.org/toc/2045-2322Abstract Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI2 reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI2 on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI2 caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI2 can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis.M. Z. YusufZ. RaslanL. AtkinsonA. AburimaS. G. ThomasK. M. NaseemS. D. J. CalaminusNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q M. Z. Yusuf Z. Raslan L. Atkinson A. Aburima S. G. Thomas K. M. Naseem S. D. J. Calaminus Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
description	Abstract Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI2 reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI2 on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI2 caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI2 can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis.
format	article
author	M. Z. Yusuf Z. Raslan L. Atkinson A. Aburima S. G. Thomas K. M. Naseem S. D. J. Calaminus
author_facet	M. Z. Yusuf Z. Raslan L. Atkinson A. Aburima S. G. Thomas K. M. Naseem S. D. J. Calaminus
author_sort	M. Z. Yusuf
title	Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
title_short	Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
title_full	Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
title_fullStr	Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
title_full_unstemmed	Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
title_sort	prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/59e911bd8ed54800bd16bc7e224dceb4
work_keys_str_mv	AT mzyusuf prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability AT zraslan prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability AT latkinson prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability AT aaburima prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability AT sgthomas prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability AT kmnaseem prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability AT sdjcalaminus prostacyclinreversesplateletstressfibreformationcausingplateletaggregateinstability
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Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability

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