Calmodulin antagonists induce platelet apoptosis |
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Authors: | Zhicheng Wang Quanwei Shi |
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Affiliation: | School of Biological Science and Medical Engineering, Beihang University, Beijing, China |
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Abstract: | Calmodulin (CaM) antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some of which have been extensively used as anti-cancer agents. In platelets, CaM has been found to bind directly to the cytoplasmic domains of several platelet receptors. Incubation of platelets with CaM antagonists impairs the receptors-related platelet functions. However, it is still unknown whether CaM antagonists induce platelet apoptosis. Here we show that CaM antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7), tamoxifen (TMX), and trifluoperazine (TFP) induce apoptotic events in human platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 activation, and phosphatidylserine exposure. CaM antagonists did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP-, botrocetin-, and α-thrombin-induced platelet aggregation, platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pre-treated with CaM antagonists. Furthermore, cytosolic Ca2+ levels were obviously elevated by both W7 and TMX, and membrane-permeable Ca2+ chelator BAPTA-AM significantly reduced apoptotic events in platelets induced by W7. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis. The elevation of the cytosolic Ca2+ levels may be involved in the regulation of CaM antagonists-induced platelet apoptosis. |
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Keywords: | CaM, calmodulin VWF, von Willebrand factor TMX, tamoxifen PS, phosphatidylserine GP, glycoprotein W7, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide BIM, Bisindolylmaleimide I hydrochloride W5, N-(6-aminohexyl)-1-naphthalenesulfonamide ΔΨm, mitochondrial inner transmembrane potential TFP, trifluoperazine TMRE, tetramethylrhodamine ethyl ester PMA, phorbol 12-myristate-13-acetate PKC, protein kinase C PRP, platelet-rich plasma |
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