Role of caspase in a subset of human platelet activation responses.
Platelets function to protect the integrity of the vascular wall. A subset of platelet activation responses that are especially important for thrombus formation include exposure of phosphatidylserine and release of microparticles, which generate procoagulant surfaces. The resemblance of these platelet activation processes to events occurring in nucleated cells undergoing apoptosis suggests a possible role for caspases, which are major effector enzymes of nucleated cell apoptosis. We demonstrate here the presence of caspase-3 in human platelets and its activation by physiological platelet agonists. Using cell-permeable specific inhibitors, we demonstrate a role for a caspase-3-like protease in the agonist-induced (collagen plus thrombin or Ca2+ ionophore) platelet activation events of phosphatidylserine exposure, microparticle release, and cleavage of moesin, a cytoskeletal-membrane linker protein. The role of caspase-3 in platelet activation is restricted rather than global, because other activation responses, alpha granule secretion, shape change, and aggregation were unaffected by caspase-3 inhibitors. Experiments with two classes of protease inhibitors show that caspase-3 function is distinct from that of calpain, which is also involved in late platelet activation events. These findings show novel functions of caspase and provide new insights for understanding of platelet activation.
Shcherbina
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The Center for Blood Research and the Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Remold-O'Donnell
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D001792:Blood Platelets / Q000201:enzymology* / Q000648:ultrastructure; D000001:Calcimycin / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000097:blood; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000097:blood*; D003094:Collagen / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008840:Microfilament Proteins / Q000097:blood; D009842:Oligopeptides / Q000494:pharmacology; D010718:Phosphatidylserines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007476:Ionophores; D008840:Microfilament Proteins; D009842:Oligopeptides; D010718:Phosphatidylserines; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C071058:moesin; D000001:Calcimycin; D003094:Collagen; D013917:Thrombin; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3; D020169:Caspases