Abstract
Antithrombin III (AT-III), an anti-coagulant, has recently been reported to directly affect human platelet functions. However, the exact mechanism of AT-III in platelets remains to be clarified. We have previously shown that adenosine diphosphate (ADP)-induced phosphorylation of heat shock protein 27 (HSP27) via p44/p42 mitogen-activated protein kinase (MAPK) and p38 MAPK is correlated with platelet granule secretion. In the present study, we investigated the relationship between AT-III and the ADP-induced platelet granule secretion. The ADP-induced secretion of platelet-derived growth factor (PDGF)-AB and serotonin (5-HT) were significantly suppressed by AT-III. The ADP-induced soluble CD40 ligand (sCD40L) release was inhibited by either PD98059, a MEK inhibitor, or SB203580, a p38 MAPK inhibitor. AT-III also inhibited the sCD40L release. AT-III markedly attenuated the ADP-induced phosphorylation levels of p44/p42 MAPK and p38 MAPK. Furthermore, the ADP-induced HSP27 phosphorylation was suppressed by AT-III. These results strongly suggest that AT-III directly acts on platelets and suppresses ADP-induced platelet granule secretion due to inhibiting HSP27 phosphorylation via p44/p42 MAPK and p38 MAPK.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Diphosphate / metabolism
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Adenosine Diphosphate / pharmacology*
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Anticoagulants / pharmacology*
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Antithrombin III / metabolism
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Antithrombin III / pharmacology*
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Blood Platelets / metabolism*
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CD40 Ligand / metabolism
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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HSP27 Heat-Shock Proteins / metabolism*
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Heat-Shock Proteins
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Humans
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Imidazoles / pharmacology
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Molecular Chaperones
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Phosphorylation / drug effects
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Platelet-Derived Growth Factor / metabolism
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Pyridines / pharmacology
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Secretory Vesicles / metabolism*
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Serotonin / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anticoagulants
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Enzyme Inhibitors
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Flavonoids
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HSP27 Heat-Shock Proteins
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HSPB1 protein, human
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Heat-Shock Proteins
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Imidazoles
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Molecular Chaperones
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Platelet-Derived Growth Factor
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Pyridines
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platelet-derived growth factor AB
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CD40 Ligand
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Serotonin
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Adenosine Diphosphate
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Antithrombin III
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one