title: Calpain activator dibucaine induces platelet apoptosis.
abstract: Calcium-dependent calpains are a family of cysteine proteases that have been demonstrated to play key roles in both platelet glycoprotein Ibα shedding and platelet activation and altered calpain activity is associated with thrombotic thrombocytopenic purpura. Calpain activators induce apoptosis in several types of nucleated cells. However, it is not clear whether calpain activators induce platelet apoptosis. Here we show that the calpain activator dibucaine induced several platelet apoptotic events including depolarization of the mitochondrial inner transmembrane potential, up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-X(L), caspase-3 activation and phosphatidylserine exposure. Platelet apoptosis elicited by dibucaine was not affected by the broad spectrum metalloproteinase inhibitor GM6001. Furthermore, dibucaine did not induce platelet activation as detected by P-selectin expression and PAC-1 binding. However, platelet aggregation induced by ristocetin or α-thrombin, platelet adhesion and spreading on von Willebrand factor were significantly inhibited in platelets treated with dibucaine. Taken together, these data indicate that dibucaine induces platelet apoptosis and platelet dysfunction.
authors: School of Biological Science and Medical Engineering, Beijing University of Aeronautics and Astronautics, 37 Xueyuan Road, Haidian District, Beijing 100083, China; E-Mails: zhangwl@be.buaa.edu.cn (W.Z.); liujuno0o@sina.com (J.L.); ruichen-sun@hotmail.com (R.S.); loveenly1314@hotmail.com (L.Z.); djsmile1987@yahoo.com.cn (J.D.).
authors: Weilin
authors: W
authors: Zhang
authors: Jun
authors: J
authors: Liu
authors: Ruichen
authors: R
authors: Sun
authors: Lili
authors: L
authors: Zhao
authors: Juan
authors: J
authors: Du
authors: Changgeng
authors: C
authors: Ruan
authors: Kesheng
authors: K
authors: Dai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D003992:Dibucaine / Q000633:toxicity*; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D054641:Dual Specificity Phosphatase 2 / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000633:toxicity*; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D012310:Ristocetin / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D004151:Dipeptides; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019007:P-Selectin; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C410340:calpain activator; D012310:Ristocetin; D054641:Dual Specificity Phosphatase 2; D013917:Thrombin; D053148:Caspase 3; D003992:Dibucaine