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Prostaglandin E2 potentiates platelet aggregation by priming protein kinase
C
R Vezza, R Roberti, GG Nenci and P Gresele
Institute of Internal and Vascular Medicine, University of Perugia, Italy.
Prostaglandin E2 (PGE2) is produced by activated platelets and by several
other cells, including capillary endothelial cells. PGE2 exerts a dual
effect on platelet aggregation: inhibitory, at high, supraphysiologic
concentrations, and potentiating, at low concentrations. No information
exists on the biochemical mechanisms through which PGE2 exerts its
proaggregatory effect on human platelets. We have evaluated the activity of
PGE2 on human platelets and have analyzed the second messenger pathways
involved. PGE2 (5 to 500 nmol/L) significantly enhanced aggregation induced
by subthreshold concentrations of U46619, thrombin, adenosine diphosphate
(ADP), and phorbol 12-myristate 13-acetate (PMA) without simultaneously
increasing calcium transients. At a high concentration (50 mumol/L), PGE2
inhibited both aggregation and calcium movements. PGE2 (5 to 500 nmol/L)
significantly enhanced secretion of beta-thromboglobulin (beta TG) and
adenosine triphosphate from U46619- and ADP-stimulated platelets, but it
did not affect platelet shape change. PGE2 also increased the binding of
radiolabeled fibrinogen to the platelet surface and increased the
phosphorylation of the 47-kD protein in 32P- labeled platelets stimulated
with subthreshold doses of U46619. Finally, the amplification of
U46619-induced aggregation by PGE2 (500 nmol/L) was abolished by four
different protein kinase C (PKC) inhibitors (calphostin C, staurosporine,
H7, and TMB8). Our results suggest that PGE2 exerts its facilitating
activity on agonist-induced platelet activation by priming PKC to
activation by other agonists. PGE2 potentiates platelet activation at
concentrations produced by activated platelets and may thus be of
pathophysiologic relevance.
Volume 82,
Issue 9,
pp. 2704-2713,
11/01/1993
Copyright © 1993 by The American Society of Hematology
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