Abstract
Although platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (∆Ψm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ∆Ψm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis*
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Biphenyl Compounds / pharmacology
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Blood Platelets / metabolism*
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Blood Platelets / pathology*
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Calcimycin / pharmacology
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Calcium / metabolism
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Collagen / metabolism
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Cytochromes c / metabolism
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Cytoplasm / metabolism
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Dose-Response Relationship, Drug
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Flow Cytometry / methods
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Ionophores / metabolism
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Membrane Potential, Mitochondrial
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Mitochondrial Proteins / metabolism*
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Serine Endopeptidases / metabolism*
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Signal Transduction*
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Sulfonamides / pharmacology
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Thrombin / metabolism
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X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
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ABT-737
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Biphenyl Compounds
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Ionophores
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Mitochondrial Proteins
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Nitrophenols
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Piperazines
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Sulfonamides
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Calcimycin
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Collagen
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Cytochromes c
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2
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Thrombin
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CASP3 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 9
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Calcium