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dc.contributor.authorEstevez, Brian
dc.contributor.authorStojanovic, Aleksandra
dc.contributor.authorDelaney, M Keegan
dc.contributor.authorO'Brien, Kelly
dc.contributor.authorBerndt, Michael
dc.contributor.authorRuan, Changgeng
dc.contributor.authorDu, Xaioping
dc.identifier.citationEstevez, Brian and Stojanovic, Aleksandra and Delaney, M Keegan and O'Brien, Kelly and Berndt, Michael and Ruan, Changgeng and Du, Xaioping. 2013. LIM kinase-1 selectively promotes glycoprotein 1b-IX-mediated TXA2 synthesis, platelet activation, and thrombosis. Blood. 121 (22): pp. 4586-4594.

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.

dc.publisherAmerican Society of Hematology
dc.titleLIM kinase-1 selectively promotes glycoprotein 1b-IX-mediated TXA2 synthesis, platelet activation, and thrombosis
dc.typeJournal Article
curtin.accessStatusOpen access via publisher

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