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Regulation of protein kinase C by nitroarachidonic acid: impact on human platelet activation

Bonilla, L., O'Donnell, Valerie Bridget, Clark, Stephen Robert, Rubbo, H. and Trostchansky, A. 2013. Regulation of protein kinase C by nitroarachidonic acid: impact on human platelet activation. Archives of Biochemistry and Biophysics 533 (1-2) , pp. 55-61. 10.1016/j.abb.2013.03.001

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Abstract

Platelet activation represents a key event in normal hemostasis as well as during platelet plug formation related to thrombosis. Nitro-fatty acids are novel endogenously produced signaling mediators exerting pluripotent anti-inflammatory actions in cells and tissues. We have recently shown that nitroarachidonic acid inhibits thromboxane synthesis during platelet activation by affecting prostaglandin endoperoxide H synthase (PGHS). Herein, we investigated the regulation of human platelet activation by NO2AA and describe a novel mechanism involving protein kinase C (PKC) inhibition. NO2AA-mediated antiplatelet effects were characterized using mass spectrometry, confocal microscopy, flow cytometry, western blot and aggregometry. Incubation of NO2AA with human platelets caused a significant reduction in platelet sensitivity to thrombin, ADP, arachidonic acid (AA), and phorbol ester (PMA). These effects were cGMP-independent and did not involve Ca2+ store-dependent mobilization. In contrast, signaling downstream of conventional PKC activation, such as α-granule secretion and extracellular signal regulated kinase 2 activation was strongly inhibited by NO2AA. Immunofluorescence confocal microscopy confirmed NO2AA-mediated inhibition of PKCα translocation to the membrane. In summary, we demonstrate that NO2AA inhibits platelet activation through modulation of PKCα activity as a potential novel mechanism for platelet regulation in vivo.

Item Type: Article
Status: Published
Schools: Cardiff Work Environment Research Centre (CWERC)
Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Eicosanoids, Inflammation, Nitro-fatty acids, PGHS, Platelets, Protein kinase C
Publisher: Elsevier
ISSN: 0003-9861
Last Modified: 04 Jun 2017 06:10
URI: http://orca.cf.ac.uk/id/eprint/56866

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