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LIM kinase-1 selectively promotes glycoprotein Ib-IX-mediated TXA2 synthesis, platelet activation, and thrombosis.
Estevez, Brian; Stojanovic-Terpo, Aleksandra; Delaney, M Keegan; O'Brien, Kelly A; Berndt, Michael C; Ruan, Changgeng; Du, Xiaoping.
Afiliação
  • Estevez B; Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA.
Blood ; 121(22): 4586-94, 2013 May 30.
Article em En | MEDLINE | ID: mdl-23620575
Current antithrombotic drugs have an adverse effect on bleeding, highlighting the need for new molecular targets for developing antithrombotic drugs that minimally affect hemostasis. Here we show that LIMK1(-/-) mice have defective arterial thrombosis in vivo but do not differ from wild-type mice with respect to bleeding time. LIMK1(-/-) mice show a selective defect in platelet activation induced through the von Willebrand Factor (VWF) receptor, the glycoprotein Ib-IX-V complex (GPIb-IX), but not by GPIb-IX-independent platelet agonists. In fact, LIMK1(-/-) platelets show an enhanced reaction to certain GPIb-IX-independent agonists. The defect of LIMK1(-/-) platelets in GPIb-IX-mediated platelet activation is attributed to a selective inhibition in VWF/GPIb-IX-induced phosphorylation of cytosolic phospholipase A2 (cPLA2) and consequent thromboxane A2 (TXA2) production. Supplementing a TXA2 analog, U46619, corrected the defect of LIMK1(-/-) platelets in VWF-induced stable platelet adhesion. Although LIMK1(-/-) platelets also showed reduced actin polymerization after GPIb-IX-mediated platelet aggregation, actin polymerization inhibitors did not reduce TXA2 generation, but rather accelerated platelet aggregation, suggesting that the role of LIMK1 in GPIb-mediated platelet activation is independent of actin polymerization. Thus, LIMK1 plays a novel role in selectively mediating GPIb-IX-dependent TXA2 synthesis and thrombosis and represents a potential target for developing antithrombotic drugs with minimal bleeding side effect.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose / Tromboxano A2 / Ativação Plaquetária / Complexo Glicoproteico GPIb-IX de Plaquetas / Quinases Lim Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Blood Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose / Tromboxano A2 / Ativação Plaquetária / Complexo Glicoproteico GPIb-IX de Plaquetas / Quinases Lim Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Blood Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos