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: Brian Estevez, Aleksandra Stojanovic-Terpo, M Keegan Delaney, Kelly A O'Brien, Michael C Berndt, Changgeng Ruan, Xiaoping Du
• Journal: Blood (Blood) Vol. 121 Issue 22 Pg. 4586-94 (May 30 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23620575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Actin Depolymerizing Factors
• Actins
• Fibrinolytic Agents
• Platelet Glycoprotein GPIb-IX Complex
• von Willebrand Factor
• Thromboxane A2
• LIMK1 protein, human
• Lim Kinases
• Limk1 protein, mouse

Topics

• Actin Depolymerizing Factors (metabolism)
• Actins (metabolism)
• Animals
• Blood Platelets (metabolism)
• Cell Adhesion (physiology)
• Drug Design
• Fibrinolytic Agents (metabolism)
• Hemorrhage (drug therapy, metabolism)
• Humans
• Lim Kinases (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Platelet Activation (physiology)
• Platelet Glycoprotein GPIb-IX Complex (metabolism)
• Stress, Mechanical
• Thrombosis (metabolism)
• Thromboxane A2 (biosynthesis, metabolism)
• von Willebrand Factor (metabolism)