Abstract 14411: LIM Kinase-1 Selectively Mediates Platelet Glycoprotein Ib-IX-Dependent Thromboxane A2 Synthesis and Platelet Activation Independent of its Role in Actin Polymerization
LIM Kinase-1 (LIMK1) regulates cytoskeletal dynamics in various cells, but its role in platelet function remains unclear. Here, we show that LIMK1-/- mice have a selective defect in platelet activation induced by the von Willebrand factor (VWF) receptor, the glycoprotein Ib-IX-V complex (GPIb-IX). GPIb-IX mediates initial platelet adhesion to subendothelial-bound von Willebrand factor (VWF) at sites of vascular injury and transduces signals leading to platelet activation, stable platelet adhesion, and thrombus formation. LIMK1-/- mice are defective in stable platelet adhesion to VWF under shear stress and for thrombosis in vivo. This defect is attributed to a loss of function in VWF/GPIb-IX-induced phosphorylation of cytosolic phospholipase A2 (cPLA2) and consequent thromboxane A2 (TXA2) production. Supplementing a TXA2 analog, U46619, corrected the defects of LIMK1-/- platelets in VWF-induced aggregation and stable platelet adhesion. Although LIMK1-/- platelets also showed defective actin polymerization following GPIb-IX-mediated platelet aggregation, actin polymerization inhibitors did not diminish TXA2 generation but rather accelerated platelet aggregation. Thus, LIMK1 plays a novel role in selectively mediating GPIb-IX-dependent platelet activation and thrombosis via a TXA2 synthesis pathway, which is independent of its role in stimulating actin polymerization.
- © 2012 by American Heart Association, Inc.