RT Journal Article
SR Electronic
T1 Protein Kinase C Regulation of 12-lipoxygenase-mediated Human Platelet Activation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.075630
DO 10.1124/mol.111.075630
A1 Jennifer Yeung
A1 Patrick L Apopa
A1 Joanne Vesci
A1 Victor Kenyon
A1 Ganesha Rai
A1 Ajit Jadhav
A1 Anton Simeonov
A1 Theodore R. Holman
A1 David J Maloney
A1 Olivier Boutaud
A1 Michael Holinstat
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/12/08/mol.111.075630.abstract
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.