title: LIM kinase-1 selectively promotes glycoprotein Ib-IX-mediated TXA2 synthesis, platelet activation, and thrombosis.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Estevez
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Stojanovic-Terpo
authors.forename: M Keegan
authors.initials: MK
authors.lastname: Delaney
authors.forename: Kelly A
authors.initials: KA
authors.lastname: O'Brien
authors.forename: Michael C
authors.initials: MC
authors.lastname: Berndt
authors.forename: Changgeng
authors.initials: C
authors.lastname: Ruan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000378:metabolism; D006470:Hemorrhage / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000502:physiology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D013314:Stress, Mechanical; D013927:Thrombosis / Q000378:metabolism*; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D005343:Fibrinolytic Agents; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D013928:Thromboxane A2; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse