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Research ArticleArticle

Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation

Jennifer Yeung, Patrick L. Apopa, Joanne Vesci, Victor Kenyon, Ganesha Rai, Ajit Jadhav, Anton Simeonov, Theodore R. Holman, David J. Maloney, Olivier Boutaud and Michael Holinstat
Molecular Pharmacology March 2012, 81 (3) 420-430; DOI: https://doi.org/10.1124/mol.111.075630
Jennifer Yeung
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Patrick L. Apopa
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Joanne Vesci
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Victor Kenyon
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Ganesha Rai
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Ajit Jadhav
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Anton Simeonov
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Theodore R. Holman
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David J. Maloney
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Olivier Boutaud
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Abstract

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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL089457, HL081009] and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [Grant MH081283].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.075630.

  • ABBREVIATIONS:

    AA
    arachidonic acid
    COX-1
    cyclooxygenase-1
    12-LOX
    12-lipoxygenase
    PLA2
    phospholipase A2
    PKC
    protein kinase C
    12-HETE
    12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid
    PAR
    protease-activated receptor
    Ro 31-8220
    3-[1-(3-(amidinothio)propyl-1H-indol-3-yl)]-3-(1-methyl-1H-indol-3-yl) maleimide (bisindolylmaleimide IX)
    PMA
    phorbol myristoyl acetate
    GPCR
    G protein-coupled receptor
    NCTT-956
    N-((8-hydroxy-5-nitroquinolin-7-yl)(thiophen-2-yl)methyl)propionamide
    ERK
    extracellular regulated kinase
    AP
    activating peptide
    FITC
    fluorescein isothiocyanate
    TxB2
    thromboxane B2
    cPLA2
    cytosolic phospholipase A2
    CVX
    convulxin
    12-HpETE
    12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid
    MAPK
    mitogen-activated protein kinase.

  • Received September 9, 2011.
  • Accepted December 8, 2011.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

PKC Regulates Platelet Activation Downstream of 12-Lipoxygenase

Jennifer Yeung, Patrick L. Apopa, Joanne Vesci, Victor Kenyon, Ganesha Rai, Ajit Jadhav, Anton Simeonov, Theodore R. Holman, David J. Maloney, Olivier Boutaud and Michael Holinstat
Molecular Pharmacology March 1, 2012, 81 (3) 420-430; DOI: https://doi.org/10.1124/mol.111.075630

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Research ArticleArticle

PKC Regulates Platelet Activation Downstream of 12-Lipoxygenase

Jennifer Yeung, Patrick L. Apopa, Joanne Vesci, Victor Kenyon, Ganesha Rai, Ajit Jadhav, Anton Simeonov, Theodore R. Holman, David J. Maloney, Olivier Boutaud and Michael Holinstat
Molecular Pharmacology March 1, 2012, 81 (3) 420-430; DOI: https://doi.org/10.1124/mol.111.075630
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