Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability

Yusuf, M. Z.; Raslan, Z.; Atkinson, L.; Aburima, A.; Thomas, S. G.; Naseem, K. M.; Calaminus, S. D.J.

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 promoted 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.

Citation

Yusuf, M. Z., Raslan, Z., Atkinson, L., Aburima, A., Thomas, S. G., Naseem, K. M., & Calaminus, S. D. (2017). Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability. Scientific reports, 7(1), Article ARTN 5582. https://doi.org/10.1038/s41598-017-05817-9

• Journal Article Type: Article
• Acceptance Date: Jun 2, 2017
• Online Publication Date: Jul 17, 2017
• Publication Date: Dec 1, 2017
• Deposit Date: Jun 28, 2017
• Publicly Available Date: Jul 17, 2017
• Journal: Scientific reports
• Print ISSN: 2045-2322
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 1
• Article Number: ARTN 5582
• DOI: https://doi.org/10.1038/s41598-017-05817-9
• Keywords: Prostacyclin; Platelets
• Public URL: https://hull-repository.worktribe.com/output/453080
• Publisher URL: https://www.nature.com/articles/s41598-017-05817-9
• Additional Information: This is a copy of an open access article published in Scientific reports, 2017, v.7.