Protein kinase C regulation of 12-lipoxygenase-mediated human platelet activation.

Yeung J, Apopa PL, Vesci J, Kenyon V, Rai G, Jadhav A, Simeonov A, Holman TR, Maloney DJ, Boutaud O, Holinstat M
Mol Pharmacol. 2012 81 (3): 420-30

PMID: 22155783 · PMCID: PMC3286293 · DOI:10.1124/mol.111.075630

Platelet activation is important in the regulation of hemostasis and thrombosis. Uncontrolled activation of platelets may lead to arterial thrombosis, which is a major cause of myocardial infarction and stroke. After activation, metabolism of arachidonic acid (AA) by 12-lipoxygenase (12-LOX) may play a significant role in regulating the degree and stability of platelet activation because inhibition of 12-LOX significantly attenuates platelet aggregation in response to various agonists. Protein kinase C (PKC) activation is also known to be an important regulator of platelet activity. Using a newly developed selective inhibitor for 12-LOX and a pan-PKC inhibitor, we investigated the role of PKC in 12-LOX-mediated regulation of agonist signaling in the platelet. To determine the role of PKC within the 12-LOX pathway, a number of biochemical endpoints were measured, including platelet aggregation, calcium mobilization, and integrin activation. Inhibition of 12-LOX or PKC resulted in inhibition of dense granule secretion and attenuation of both aggregation and αIIbβ(3) activation. However, activation of PKC downstream of 12-LOX inhibition rescued agonist-induced aggregation and integrin activation. Furthermore, inhibition of 12-LOX had no effect on PKC-mediated aggregation, indicating that 12-LOX is upstream of PKC. These studies support an essential role for PKC downstream of 12-LOX activation in human platelets and suggest 12-LOX as a possible target for antiplatelet therapy.

MeSH Terms (13)

Arachidonate 12-Lipoxygenase Blood Platelets Blotting, Western Calcium Enzyme Activation Flow Cytometry Gas Chromatography-Mass Spectrometry Humans Lipoxygenase Inhibitors Platelet Activation Platelet Glycoprotein GPIIb-IIIa Complex Protein Kinase C Protein Kinase Inhibitors

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