title: Activation of caspases-9, -3 and -8 in human platelets triggered by BH3-only mimetic ABT-737 and calcium ionophore A23187: caspase-8 is activated via bypass of the death receptors.
abstract: Platelet apoptosis and activation have been studied in human platelets treated with BH3-only mimetic ABT-737 and calcium ionophore A23187, agents triggering apoptosis through the intrinsic mitochondrial pathway. Platelet apoptosis was determined as activation of crucial apoptosis-associated caspases, initiator caspase-9 of intrinsic apoptosis pathway, executioner caspase-3 and initiator caspase-8 of extrinsic death receptor pathway, and platelet activation was detected by P-selectin (CD62) exposure on the platelet surface. We found that ABT-737 predominantly induced activation of caspases-9, -3 and -8 rather than CD62 exposure, whereas A23187 induces both caspases activation and CD62 exposure. Caspase-8 activation was stimulated independently of the extrinsic apoptosis pathway via mitochondrial membrane permeabilization and depolarization. These data suggest that (i) caspase-8 activation is triggered in ABT-737- and A23187-treated anucleate platelets through the mitochondria-initiated caspase activation cascade bypassing the death receptors, and (ii) ABT-737-treated platelets are a useful experimental tool for discerning the role of platelet apoptosis in platelet function and survival.
authors.affiliation: Division of Transfusion Medicine, Department of Laboratory Medicine, The Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: Asuman
authors.initials: A
authors.lastname: Mutlu
authors.forename: Armen V
authors.initials: AV
authors.lastname: Gyulkhandanyan
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.forename: Valery
authors.initials: V
authors.lastname: Leytin
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D040761:Biomimetic Materials / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D000001:Calcimycin / Q000494:pharmacology*; D061207:Calcium Ionophores / Q000494:pharmacology*; D020169:Caspases / Q000097:blood*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D053218:Receptors, Death Domain / Q000097:blood*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D061207:Calcium Ionophores; D007527:Isoenzymes; D009596:Nitrophenols; D010879:Piperazines; D053218:Receptors, Death Domain; D013449:Sulfonamides; D000001:Calcimycin; D020169:Caspases