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Title: The role of glucocorticoids in platelet function
Author: Banerjee, Sreemoti
ISNI:       0000 0004 5363 6491
Awarding Body: University of Hull and the University of York
Current Institution: University of Hull
Date of Award: 2014
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Platelets are pivotal in regulating haemostasis, but can precipitate atherothrombosis associated to cardiovascular diseases. The synthetic glucocorticoid prednisolone is widely used as an anti-inflammatory and immunosuppressive drug. Previously it was shown that prednisolone inhibited platelet aggregation and adhesion under conditions of flow, although the mechanisms remained unclear. In the present study we examined the mechanisms responsible for the inhibitory effects of prednisolone on thrombin‐mediated platelet activation. Prednisolone caused concentration‐dependent inhibition of thrombin‐induced platelet aggregation. The inhibition of aggregation by prednisolone was rapid suggesting a non‐genomic mode of action of the glucocorticoid on platelets. Prednisolone also targeted the protease‐activated receptors PAR1 and PAR4 that mediate platelet activation following thrombin stimulation. Thrombin triggers two distinct signalling cascades in platelets resulting in the phosphorylation of myosin light chains (MLC). One of these pathways is calcium‐dependent, while the other is RhoA/ROCK‐dependent. In order to understand the molecular mechanism underpinning the inhibitory effects of prednisolone, we examined the RhoA/ROCK pathway. Stimulation of platelets with thrombin led to the RhoA/RhoA kinase (ROCK)‐dependent phosphorylation of MLC. Pre‐treatment of platelets with prednisolone caused a concentration‐dependent inhibition of MLC‐ser¹⁹ phosphorylation. The inhibition was rapid and transient. Consistent with this observation, prednisolone also reduced the inhibitory phosphorylation of the myosin light chain phosphatase (MLCP) at two key residues thr⁶⁹⁶ and thr⁸⁵³. In all cases the effects of prednisolone were inhibited by the glucocorticoid receptor antagonist RU486. Finally, prednisolone also inhibited RhoA activation in platelets following thrombin stimulation. Thus, prednisolone inhibited platelet activation by targeting RhoA/ROCK‐mediated signalling events following thrombin stimulation. Modulation of the RhoA activity represents one of the non‐genomic effects of this synthetic glucocorticoid on platelets and these might have important clinical implications in the treatment of cardiovascular diseases.
Supervisor: Naseem, Khalid Sponsor: University of Hull ; Heart Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine