PT - JOURNAL ARTICLE AU - Jennifer Yeung AU - Patrick L. Apopa AU - Joanne Vesci AU - Victor Kenyon AU - Ganesha Rai AU - Ajit Jadhav AU - Anton Simeonov AU - Theodore R. Holman AU - David J. Maloney AU - Olivier Boutaud AU - Michael Holinstat TI - Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation AID - 10.1124/mol.111.075630 DP - 2012 Mar 01 TA - Molecular Pharmacology PG - 420--430 VI - 81 IP - 3 4099 - http://molpharm.aspetjournals.org/content/81/3/420.short 4100 - http://molpharm.aspetjournals.org/content/81/3/420.full SO - Mol Pharmacol2012 Mar 01; 81 AB - 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 αIIbβ3 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.