TY - JOUR
T1 - Antithrombotic Potential of Blockers of Store-Operated Calcium Channels in Platelets
AU - van Kruchten, Roger
AU - Braun, Attila
AU - Feijge, Marion A. H.
AU - Kuijpers, Marijke J. E.
AU - Rivera-Galdos, Ronmy
AU - Kraft, Peter
AU - Stoll, Guido
AU - Kleinschnitz, Christoph
AU - Bevers, Edouard M.
AU - Nieswandt, Bernhard
AU - Heemskerk, Johan W. M.
PY - 2012/7
Y1 - 2012/7
N2 - 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.)
AB - 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.)
KW - thrombosis
KW - platelets
KW - calcium channel blockers
KW - stroke
KW - pharmacology
U2 - 10.1161/ATVBAHA.111.243907
DO - 10.1161/ATVBAHA.111.243907
M3 - Article
C2 - 22580895
SN - 1079-5642
VL - 32
SP - 1717
EP - 1723
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 7
ER -