Platelet particle formation by anti–GPIIIa49-66 Ab, Ca2+ ionophore A23187, and phorbol myristate acetate is induced by reactive oxygen species and inhibited by dexamethasone blockade of platelet phospholipase A2, 12-lipoxygenase, and NADPH oxidase
| Autor: | Simon Karpatkin, Yelena Gor, Michael A. Nardi, Fang Xu, Steven J. Feinmark |
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| Rok vydání: | 2007 |
| Předmět: |
Blood Platelets
Immunology Anti-Inflammatory Agents Oxidative phosphorylation Arachidonate 12-Lipoxygenase Biochemistry Dexamethasone Phospholipases A Mice Lipoxygenase Cytosol Phospholipase A2 Animals Humans Platelet Lipoxygenase Inhibitors Calcimycin Immunobiology Mice Knockout chemistry.chemical_classification Reactive oxygen species NADPH oxidase Ionophores biology Chemistry Group IV Phospholipases A2 Cell Membrane Integrin beta3 Antibodies Monoclonal NADPH Oxidases Cell Biology Hematology Thrombocytopenia Mice Inbred C57BL Phospholipases A2 Protein Transport Tetradecanoylphorbol Acetate Carcinogens biology.protein Reactive Oxygen Species Oxidation-Reduction |
| Zdroj: | Blood. 110:1989-1996 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | An HIV antibody (Ab) against platelet integrin GPIIIa49-66 induces complement-independent platelet particle formation by the elaboration of reactive oxygen species (ROS) downstream of the activation of the platelet NADPH oxidase by the 12-lipoxygenase (12-LO) product 12(S)-HETE. To determine whether other inducers of platelet particle formation also function via the induction of ROS, we examined the effects of the Ca2+ ionophore A23187 and phorbol myristate acetate (PMA). Both agents induced oxidative platelet particle formation in an identical fashion as Ab, requiring Ca2+ flux and 12(S)-HETE production as well as intact NADPH oxidase and 12-LO pathways. Since HIV-ITP patients with this Ab correct their platelet counts with dexamethasone (Dex), we examined the role of this steroid in this unique autoimmune disorder. Dex at therapeutic concentrations inhibited Ab-, A23187-, or PMA-induced platelet particle formation by inhibiting platelet PLA2, 12-LO, and NADPH oxidase. The operational requirement of translocation of PLA2, 12-LO, and NADPH oxidase components (p67 phox) from cytosol to membrane for induction of ROS was both inhibited and partially reversed by Dex in platelets. We conclude that (1) platelet particle formation can be induced by the generation of ROS; and (2) platelet PLA2, 12-LO, NADPH oxidase, and cytosol membrane translocation, requirements for ROS production, are inhibited by Dex. |
| Databáze: | OpenAIRE |
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