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  - 2011 Dec 09
TA  - Molecular Pharmacology
PG  - mol.111.075630
4099  - http://molpharm.aspetjournals.org/content/early/2011/12/08/mol.111.075630.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/12/08/mol.111.075630.full
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. Following 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 as 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 anti-platelet therapy.