Antithrombin III suppresses ADP-induced platelet granule secretion: inhibition of HSP27 phosphorylation.
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.
Doi
Tomoaki
T
Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Adachi
Seiji
S
Takai
Shinji
S
Matsushima-Nishiwaki
Rie
R
Kato
Hisaaki
H
Enomoto
Yukiko
Y
Minamitani
Chiho
C
Otsuka
Takanobu
T
Tokuda
Haruhiko
H
Akamatsu
Shigeru
S
Iwama
Toru
T
Kozawa
Osamu
O
Ogura
Shinji
S
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D000990:Antithrombin III / Q000378:metabolism / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018832:Molecular Chaperones; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D022142:Secretory Vesicles / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007093:Imidazoles; D018832:Molecular Chaperones; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; C095477:platelet-derived growth factor AB; D023201:CD40 Ligand; D012701:Serotonin; D000244:Adenosine Diphosphate; D000990:Antithrombin III; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one