2-aminoethoxydiphenylborate (2-APB) inhibits release of phosphatidylserine-exposing extracellular vesicles from platelets
Cell Death Discovery
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Harper, M., Davies, J., & Wei, H. (2020). 2-aminoethoxydiphenylborate (2-APB) inhibits release of phosphatidylserine-exposing extracellular vesicles from platelets. Cell Death Discovery, 6 (20)https://doi.org/10.1038/s41420-020-0244-9
Activated, procoagulant platelets shed phosphatidylserine (PS)-exposing extracellular vesicles (EVs) from their surface in a Ca2+- and calpain-dependent manner. These PS-exposing EVs are prothrombotic and proinflammatory and are found at elevated levels in many cardiovascular and metabolic diseases. How PS-exposing EVs are shed is not fully understood. A clearer understanding of this process may aid the development of drugs to selectively block their release. In this study we report that 2-aminoethoxydiphenylborate (2-APB) significantly inhibits the release of PS-exposing EVs from platelets stimulated with the Ca2+ ionophore, A23187, or the pore-forming toxin, streptolysin-O. Two analogues of 2-APB, diphenylboronic anhydride (DPBA) and 3-(diphenylphosphino)-1-propylamine (DP3A), inhibited PS-exposing EV release with similar potency. Although 2-APB and DPBA weakly inhibited platelet PS exposure and calpain activity, this was not seen with DP3A despite inhibiting PS-exposing EV release. These data suggest that there is a further target of 2-APB, independent of cytosolic Ca2+ signalling, PS exposure and calpain activity, that is required for PS-exposing EV release. DP3A is likely to inhibit the same target, without these other effects. Identifying the target of 2-APB, DPBA and DP3A may provide a new way to inhibit PS-exposing EV release from activated platelets and inhibit their contribution to thrombosis and inflammation.
J.E.D. was supported by British Heart Foundation Project Grant PG/16/45/32152 to M.T.H. Work in Dr. Harper’s lab was also supported by Wellcome Trust Seed Award 200702/Z/16/Z and Royal Society Research Grant RG170381.
WELLCOME TRUST (200702/Z/16/Z)
British Heart Foundation (PG/16/45/32152)
Royal Society (RG170381)
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External DOI: https://doi.org/10.1038/s41420-020-0244-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299891
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/