12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.

Paradigms and Technologies
Therapeutic Approaches

Abstract

Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist-specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation.

Authors

Yeung, J; Apopa, P L; Vesci, J; Stolla, M; Rai Bantukallu, Ganesha; Simeonov, Anton; Jadhav, A; Fernandez-Perez, P; Maloney, D J; Boutaud, O; Holman, T R; Holinstat, M;

Keywords

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/ chemistry
  • Animals
  • Arachidonate 12-Lipoxygenase/ metabolism
  • Blood Platelets/ metabolism
  • Cyclooxygenase 1/ metabolism
  • Eicosanoids/ metabolism
  • Flow Cytometry
  • Humans
  • Mice
  • Mice, Transgenic
  • Platelet Activation
  • Platelet Adhesiveness
  • Platelet Aggregation
  • Platelet Membrane Glycoproteins/ metabolism
  • Receptors, Thrombin/ metabolism
  • Thrombosis/ metabolism
  • Time Factors

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