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Anti-platelet properties of Pim kinase inhibition is mediated through disruption of thromboxane A2 receptor signalling

Unsworth, A. J., Bye, A. P., Sage, T., Gaspar, R. S., Eaton, N., Drew, C., Stainer, A., Kriek, N., Volberding, P. J., Hutchinson, J. L., Riley, R., Jones, S., Mundell, S. J., Cui, W., Falet, H. and Gibbins, J. M. (2020) Anti-platelet properties of Pim kinase inhibition is mediated through disruption of thromboxane A2 receptor signalling. Haematologica, 105 (6). ISSN 1592-8721 (In Press)

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To link to this item DOI: 10.3324/haematol.2019.223529

Abstract/Summary

Pim kinases are upregulated in several forms of cancer, contributing to cell survival and tumour development, but their role in platelet function and thrombotic disease has not been explored. We report for the first time that Pim-1 kinase is expressed in human and mouse platelets. Genetic deletion or pharmacological inhibition of Pim kinase results in reduced thrombus formation but is not associated with impaired haemostasis. Attenuation of thrombus formation was found to be due to inhibition of the thromboxane A2 receptor as effects on platelet function was non-additive to inhibition caused by the cyclooxygenase inhibitor indomethacin or thromboxane A2 receptor antagonist GR32191. Treatment with Pim kinase inhibitors caused reduced surface expression of the thromboxane A2 receptor and resulted in reduced responses to thromboxane A2 receptor agonists, indicating a role for Pim kinase in the regulation of thromboxane A2 receptor function. Our research identifies a novel, Pim kinase dependent regulatory mechanism for the thromboxane A2 receptor and represents a new targeting strategy that is independent of COX- 1 inhibition or direct antagonism of the thromboxane A2 receptor that whilst attenuating thrombosis does not increase bleeding.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:90919
Publisher:Ferrata Storti Foundation

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