Arsenic trioxide-mediated antiplatelet activity: pivotal role of the phospholipase Cγ2-protein kinase C-p38 MAPK cascade

Kuan H. Lin, Yi F. Chang, Chiao Y. Fan, Thanasekaran Jayakumar, Jie J. Lee, Duen S. Chou, George Hsiao, Joen Rong Sheu

研究成果: 雜誌貢獻文章同行評審

5 引文 斯高帕斯(Scopus)

摘要

Arsenic trioxide produces high rates of complete clinical remission in patients with relapsed/refractory acute promyelocytic leukemia. Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases. Few studies have examined the effects of arsenic trioxide on platelets, and the mechanisms underlying the signaling pathways remain obscure. The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation. Arsenic trioxide (5 μmol/L) exhibited more potent activity at inhibiting collagen (1 μg/mL)-induced platelet aggregation than other agonists. Arsenic trioxide (15 and 25 μmol/L) inhibited collagen-induced platelet activation accompanied by [Ca+2]i mobilization, thromboxane A2 (TxA2) formation, phospholipase C (PLC)γ2 phosphorylation, and protein kinase C (PKC) activation. Arsenic trioxide (15 and 25 μmol/L) did not significantly affect cyclic nucleotide-induced vasodilator-stimulated phosphoprotein phosphorylation. Moreover, arsenic trioxide markedly inhibited p38 mitogen-activated protein kinase (MAPK) but not JNK1/2 or ERK2 phosphorylation in washed platelets. Arsenic trioxide also markedly reduced hydroxyl radical (OH·) formation in the erythrocyte sedimentation rate (ESR) study. The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the PLCγ2-PKC-p38 MAPK cascade, thereby leading to inhibition of [Ca+2]i or free radical formation, and finally the inhibition of platelet aggregation.
原文英語
頁(從 - 到)97-108
頁數12
期刊Translational Research
155
發行號2
DOIs
出版狀態已發佈 - 二月 2010

ASJC Scopus subject areas

  • 公共衛生、環境和職業健康
  • 生物化學(醫學)
  • 生理學(醫學)

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