title: Omi/HtrA2 and XIAP are components of platelet apoptosis signalling.
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.
authors.affiliation: Division of Haematology and Children's Research Center, University Children's Hospital Zurich, and Zurich Center for Integrative Human Physiology, University of Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Winkler
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Rand
authors.forename: Markus
authors.initials: M
authors.lastname: Schmugge
authors.forename: Oliver
authors.initials: O
authors.lastname: Speer
mesh_terms: D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D007476:Ionophores / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D007476:Ionophores; D024101:Mitochondrial Proteins; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000001:Calcimycin; D003094:Collagen; D045304:Cytochromes c; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; D013917:Thrombin; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D002118:Calcium