Antithrombotic Potential of Blockers of Store-Operated Calcium Channels in Platelets

Roger van Kruchten, Attila Braun, Marion A. H. Feijge, Marijke J. E. Kuijpers, Ronmy Rivera-Galdos, Peter Kraft, Guido Stoll, Christoph Kleinschnitz, Edouard M. Bevers, Bernhard Nieswandt, Johan W. M. Heemskerk*

*Corresponding author for this work

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Abstract

Objective-Platelet Orai1 channels mediate store-operated Ca2+ entry (SOCE), which is required for procoagulant activity and arterial thrombus formation. Pharmacological blockage of these channels may provide a novel way of antithrombotic therapy. Therefore, the thromboprotective effect of SOCE blockers directed against platelet Orai1 is determined. Methods and Results-Candidate inhibitors were screened for their effects on SOCE in washed human platelets. Tested antagonists included the known compounds, SKF96365, 2-aminoethyl diphenylborate, and MRS1845 and the novel compounds, Synta66 and GSK-7975A. The potency of SOCE inhibition was in the order of Synta66>2-aminoethyl diphenylborate>GSK-7975A>SKF96365>MRS1845. The specificity of the first 3 compounds was verified with platelets from Orai1-deficient mice. Inhibitory activity on procoagulant activity and high-shear thrombus formation was assessed in plasma and whole blood. In the presence of plasma, all 3 compounds suppressed platelet responses and restrained thrombus formation under flow. Using a murine stroke model, arterial thrombus formation was provoked in vivo by transient middle cerebral artery occlusion. Postoperative administration of 2-aminoethyl diphenylborate markedly diminished brain infarct size. Conclusion-Plasma-soluble SOCE blockers such as 2-aminoethyl diphenylborate suppress platelet-dependent coagulation and thrombus formation. The platelet Orai1 channel is a novel target for preventing thrombotic events causing brain infarction. (Arterioscler Thromb Vasc Biol. 2012;32:1717-1723.)
Original languageEnglish
Pages (from-to)1717-1723
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume32
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • thrombosis
  • platelets
  • calcium channel blockers
  • stroke
  • pharmacology

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