Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP

Barbara Coles, Allison Bloodsworth, Jason P. Eiserich, Marcus J. Coffey, Rachel M. McLoughlin, John C. Giddings, Malcolm J. Lewis, Richard J. Haslam, Bruce A. Freeman, Valerie B. O'Donnell

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Reactive species formed from nitric oxide (NO) nitrate unsaturated fatty acids such as linoleate (LA) to nitrated derivatives including nitrolinoleate (LNO2). The effect of LNO2 on human platelets was examined to define how nitrated lipids might behave in vivo. LNO2, but not LA or 3-nitrotyrosine, dose dependently (0.5-10 μM) inhibited thrombin-mediated aggregation of washed human platelets, with concomitant attenuation of P-selectin expression and selective phosphorylation of VASP at the cAMP-dependent protein kinase selective site, serine 157. LNO2 caused slight mobilization of calcium (Ca2+) from intracellular stores but significantly inhibited subsequent thrombin-stimulated Ca2+ elevations. LNO2 did not elevate platelet cGMP, and its effects were not blocked with inhibitors of NO signaling (oxyhemoglobin, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. 2-fold elevations in cAMP were found following LNO2 treatment of platelets, and the adenylyl cyclase inhibitors 2′,5′-dideoxyadenosine and SQ22536 partially restored thrombin-stimulated aggregation. Finally, LNO2 significantly inhibited cAMP hydrolysis to AMP by platelet lysates. These data implicate cAMP in the anti-aggregatory action of LNO2. The platelet inhibitory actions of LNO2 indicate that nitration reactions that occur following NO generation in an oxidizing environment can alter the activity of lipids and lend insight into mechanisms by which NO-derived species may modulate the progression of vascular injury.

Original languageEnglish (US)
Pages (from-to)5832-5840
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number8
DOIs
StatePublished - Feb 22 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Coles, B., Bloodsworth, A., Eiserich, J. P., Coffey, M. J., McLoughlin, R. M., Giddings, J. C., Lewis, M. J., Haslam, R. J., Freeman, B. A., & O'Donnell, V. B. (2002). Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP. Journal of Biological Chemistry, 277(8), 5832-5840. https://doi.org/10.1074/jbc.M105209200