Antithrombotic potential of blockers of store-operated calcium channels in platelets

Arteriosclerosis, Thrombosis, and Vascular Biology
Roger van KruchtenJohan W M Heemskerk

Abstract

Platelet Orai1 channels mediate store-operated Ca(2+) 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. 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 ...Continue Reading

References

Oct 15, 1990·The Biochemical Journal·J E MerrittT J Rink
Aug 3, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Martin D BootmanClaire M Peppiatt
Jan 16, 2003·Biochemical Pharmacology·Jacquie L HarperJohn W Daly
Mar 11, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jocelyn M AugerJohan W M Heemskerk
Apr 23, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·Jeffrey F W KeurenTheo Lindhout
Jul 26, 2005·Trends in Cardiovascular Medicine·Johan W M HeemskerkPia R M Siljander
Oct 29, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·Imke C A MunnixJohan W M Heemskerk
Sep 1, 2007·Arteriosclerosis, Thrombosis, and Vascular Biology·Imke C A MunnixJohan W M Heemskerk
Jun 19, 2008·The Journal of Experimental Medicine·David Varga-SzaboBernhard Nieswandt
Oct 28, 2008·Blood·Wolfgang BergmeierStefan Feske
May 9, 2009·Journal of Thrombosis and Haemostasis : JTH·D Varga-SzaboB Nieswandt

❮ Previous
Next ❯

Citations

Jul 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Julia V GerasimenkoOle H Petersen
Jul 13, 2013·Thrombosis and Haemostasis·F LangO Borst
Jun 14, 2018·Physiology·Baptiste RodeChristelle Guibert
Jul 19, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Marshall MazepaDougald Monroe
Jan 15, 2020·Blood Advances·Nima AbbasianMatthew T Harper
Oct 21, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nadine J A MattheijJohan W M Heemskerk
Jun 30, 2012·Journal of Thrombosis and Haemostasis : JTH·M P Mahaut-Smith
Oct 28, 2019·Current Molecular Pharmacology·Melvin N RosalezMarvin A Soriano-Ursúa
Dec 18, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ulrike KaufmannStefan Feske
Sep 21, 2018·Blood Advances·Constance C F M J BaatenJohan W M Heemskerk
Oct 17, 2018·International Journal of Molecular Sciences·Mélanie LambertFabrice Antigny
Aug 7, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Ke MaFlorian Lang
Apr 7, 2018·Frontiers in Molecular Neuroscience·Agnese SecondoDiana Amantea
Feb 14, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Anke LöhndorfAndreas H Guse
Mar 13, 2021·Journal of Clinical Laboratory Analysis·Yaxin ChuRui Qiao
Jun 15, 2021·Frontiers in Pharmacology·Xiaojing LiangWeidong Han
Nov 11, 2021·Pflügers Archiv : European journal of physiology·Rosita StanzioneSperanza Rubattu

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.