Doi Tomoaki, Adachi Seiji, Takai Shinji, Matsushima-Nishiwaki Rie, Kato Hisaaki, Enomoto Yukiko, Minamitani Chiho, Otsuka Takanobu, Tokuda Haruhiko, Akamatsu Shigeru, Iwama Toru, Kozawa Osamu, Ogura Shinji
Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Arch Biochem Biophys. 2009 Sep;489(1-2):62-7. doi: 10.1016/j.abb.2009.07.009. Epub 2009 Jul 23.
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.
抗凝血酶III（AT-III）是一种抗凝剂，最近有报道称其可直接影响人类血小板功能。然而，AT-III在血小板中的具体机制仍有待阐明。我们之前已经表明，二磷酸腺苷（ADP）通过p44/p42丝裂原活化蛋白激酶（MAPK）和p38 MAPK诱导热休克蛋白27（HSP27）磷酸化，这与血小板颗粒分泌相关。在本研究中，我们调查了AT-III与ADP诱导的血小板颗粒分泌之间的关系。AT-III显著抑制了ADP诱导的血小板衍生生长因子（PDGF）-AB和5-羟色胺（5-HT）的分泌。ADP诱导的可溶性CD40配体（sCD40L）释放受到MEK抑制剂PD98059或p38 MAPK抑制剂SB203580的抑制。AT-III也抑制了sCD40L的释放。AT-III显著减弱了ADP诱导的p44/p42 MAPK和p38 MAPK的磷酸化水平。此外，AT-III抑制了ADP诱导的HSP27磷酸化。这些结果有力地表明，AT-III直接作用于血小板，并通过抑制p44/p42 MAPK和p38 MAPK介导的HSP27磷酸化来抑制ADP诱导的血小板颗粒分泌。
