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 Citations (Scopus)

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

Fingerprint

Phosphorylation
Platelet Activation
Platelets
Blood Platelets
Chemical activation
Calcium
Nitric Oxide
Thrombin
Linoleic Acid
Agglomeration
Dideoxyadenosine
Oxadiazoles
Nitration
Lipids
Quinoxalines
Oxyhemoglobins
P-Selectin
Vascular System Injuries
Adenosine Monophosphate
Cyclic AMP-Dependent Protein Kinases

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP. / Coles, Barbara; Bloodsworth, Allison; Eiserich, Jason P.; Coffey, Marcus J.; McLoughlin, Rachel M.; Giddings, John C.; Lewis, Malcolm J.; Haslam, Richard J.; Freeman, Bruce A.; O'Donnell, Valerie B.

In: Journal of Biological Chemistry, Vol. 277, No. 8, 22.02.2002, p. 5832-5840.

Research output: Contribution to journalArticle

Coles, B, Bloodsworth, A, Eiserich, JP, Coffey, MJ, McLoughlin, RM, Giddings, JC, Lewis, MJ, Haslam, RJ, Freeman, BA & O'Donnell, VB 2002, 'Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP', Journal of Biological Chemistry, vol. 277, no. 8, pp. 5832-5840. https://doi.org/10.1074/jbc.M105209200
Coles, Barbara ; Bloodsworth, Allison ; Eiserich, Jason P. ; Coffey, Marcus J. ; McLoughlin, Rachel M. ; Giddings, John C. ; Lewis, Malcolm J. ; Haslam, Richard J. ; Freeman, Bruce A. ; O'Donnell, Valerie B. / Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 8. pp. 5832-5840.
@article{98c98c13561248dea965acb57bf6feae,
title = "Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP",
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.",
author = "Barbara Coles and Allison Bloodsworth and Eiserich, {Jason P.} and Coffey, {Marcus J.} and McLoughlin, {Rachel M.} and Giddings, {John C.} and Lewis, {Malcolm J.} and Haslam, {Richard J.} and Freeman, {Bruce A.} and O'Donnell, {Valerie B.}",
year = "2002",
month = "2",
day = "22",
doi = "10.1074/jbc.M105209200",
language = "English (US)",
volume = "277",
pages = "5832--5840",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "8",

}

TY - JOUR

T1 - Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP

AU - Coles, Barbara

AU - Bloodsworth, Allison

AU - Eiserich, Jason P.

AU - Coffey, Marcus J.

AU - McLoughlin, Rachel M.

AU - Giddings, John C.

AU - Lewis, Malcolm J.

AU - Haslam, Richard J.

AU - Freeman, Bruce A.

AU - O'Donnell, Valerie B.

PY - 2002/2/22

Y1 - 2002/2/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=18544380386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18544380386&partnerID=8YFLogxK

U2 - 10.1074/jbc.M105209200

DO - 10.1074/jbc.M105209200

M3 - Article

C2 - 11748216

AN - SCOPUS:18544380386

VL - 277

SP - 5832

EP - 5840

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 8

ER -