Antiplatelet action of indirubin-3'-monoxime through suppression of glycoprotein VI-mediated signal transduction: a possible role for ERK signaling in platelets.
Vascul Pharmacol
; 63(3): 182-92, 2014 Dec.
Article
em En
| MEDLINE
| ID: mdl-25451564
ABSTRACT
We investigated the antiplatelet activity of indirubin-3'-monoxime (I3O) and the underlying mechanisms. In a rat carotid artery injury model, oral administration (20 mg/kg/day) of I3O for 3 days significantly prolonged occlusion time, and ADP- and collagen-induced platelet aggregation. In washed platelets in vitro, I3O potently inhibited collagen-induced platelet aggregation by suppressing phospholipase Cγ2 (PLCγ2) phosphorylation, subsequently blocking diacylglycerol and arachidonic acid (AA) formation, P-selectin secretion and the production of thromboxane B2. Platelet aggregation induced by phorbol-12-myristate 13-acetate, a protein kinase C (PKC) activator, was inhibited by I3O. Both I3O and U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, markedly reduced collagen-induced phosphorylation of ERK1/2 and p47, resulting in the blockade of cyclooxygenase (COX)-mediated AA metabolite production in AA-treated platelets. I3O suppressed phosphorylation of JNK, p38, GSK-3ß, and AKT. I3O inhibited glycoprotein VI (GPVI), as a collagen receptor, by suppressing the phosphorylation of tyrosine kinase Syk of GPVI and the phosphorylation of PLCγ2 and ERK1/2 stimulated by convulxin, as a specific stimulator. Our results indicate that an antiplatelet effect of I3O is due to the suppression of GPVI-mediated signaling pathways. In collagen-stimulated platelets, ERK1/2 phosphorylation is adenylyl cyclase-dependent and leads to the modulation of PKC-p47 signaling and COX-1-mediated AA-metabolic pathways.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oximas
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Plaquetas
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Glicoproteínas da Membrana de Plaquetas
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Transdução de Sinais
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Sistema de Sinalização das MAP Quinases
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Indóis
Limite:
Animals
Idioma:
En
Revista:
Vascul Pharmacol
Ano de publicação:
2014
Tipo de documento:
Article