Stimulation of tissue plasminogen activator production by retinoic acid:
synergistic effect on protein kinase C-mediated activation
RD Medh, L Santell and EG Levin
Department of Molecular and Experimental Medicine, Scripps Research
Institute, La Jolla, CA 92037.
Trans retinoic acid (t-RA) stimulated the production of tissue plasminogen
activator (tPA) in HeLa-S3 and human umbilical vein endothelial cells
(huvecs) in a dose-dependent manner with maximal release (four to five
times control) at 40 nmol/L and 40 mumol/L, respectively. In endothelial
cells, the stimulation of tPA production by phorbol 12-myristate 13-acetate
(PMA) was potentiated 1.9-fold by 10 mumol/L t-RA, or 1.8 times the
additive effect. In HeLa cells, total tPA secretion with 10 nmol/L PMA was
increased from 43 ng/mL to 96 ng/mL by 40 nmol/L t-RA, which was two times
the additive effect. Higher concentrations of t-RA (400 nmol/L) depressed
tPA secretion by itself and also suppressed PMA-induced tPA production by
50%. Histamine and thrombin also synergized with t-RA. t-RA (40 nmol/L) and
10 micrograms/mL histamine or 10 U/mL thrombin combined to induce tPA
production 3.4 and 1.3 times the additive effect in HeLa cells. Cyclic
adenosine monophosphate (cAMP) levels were not significantly affected by 10
nmol/L to 10 mumol/L t-RA. Nor did 10 nmol/L PMA and 40 nmol/L t- RA
together affect cAMP levels, suggesting that t-RA-mediated potentiation of
PMA-induced tPA production occurred via a mechanism that was independent of
cAMP levels. Downregulation of protein kinase C (PKC) by pretreatment of
huvecs with 100 nmol/L PMA completely blocked a secondary response to PMA,
but did not have a significant effect on t- RA induction. Pretreatment with
10 mumol/L t-RA, on the other hand, did not significantly affect a
secondary stimulus by 100 nmol/L PMA, but completely suppressed a secondary
stimulation by 10 mumol/L t-RA alone. These studies suggest that the
mechanism mediating t-RA stimulation of tPA production interacts with the
PKC pathway, resulting in synergism.
Volume 80,
Issue 4,
pp. 981-987,
08/15/1992
Copyright © 1992 by The American Society of Hematology
