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Vol. 53, Issue 4, 630-637, April 1998
and/or 
Enhances
Transcription of the Human Endothelial Nitric Oxide Synthase Gene
Department of Pharmacology, Johannes Gutenberg University, 55101 Mainz, Germany (H.L., T.W., I.I.-B., U.F., H.K.),
Department of
Physiological Chemistry, In primary human umbilical vein endothelial cells (HUVECs), incubation
with phorbol-12-myristate-13-acetate (PMA) enhanced basal and
bradykinin-stimulated nitric oxide production. In the HUVEC-derived
cell line EA.hy 926, PMA and phorbol-12,13-dibutyrate stimulated
endothelial nitric oxide synthase (NOS III) mRNA expression in a
concentration- and time-dependent manner. Maximal mRNA expression (3.3-fold increase) was observed after 18 hr. NOS III protein and
activity were increased to a similar extent. The specific protein
kinase C (PKC) inhibitors bisindolylmaleimide I (1 µM), Gö 6976 [12-(2cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole] (1 µM), Ro-31-8220
[3-[1-[3(amidinothio)propyl-1H-inoyl-3-yl]3-(1-methyl-1H-indoyl-3-yl) maleimide
methane sulfonate] (1 µM), and chelerythrine (3 µM) did not change NOS III expression when applied alone,
but they all prevented the up-regulation of NOS III mRNA produced by
PMA. Of the PKC isoforms expressed in EA.hy 926 cells (
, 
I, 
,
, 
, 
, 
, and µ), only PKC and PKC showed changes in
protein expression after PMA treatment. Incubation of EA.hy 926 cells with PMA for 2-6 hr resulted in a translocation of PKC and PKC from the cytosol to the cell membrane, indicating activation of these
isoforms. After 24 hr of PMA incubation, both isoforms were down-regulated. The time course of activation and down-regulation of
these two PKC isoforms correlated well with the PMA-stimulated increase
in NOS III expression. When human endothelial cells (ECV 304 or EA.hy
926) were transiently or stably transfected with a 3.5-kb fragment of
the human NOS III promoter driving a luciferase reporter gene, PMA
stimulated promoter activity up to 2.5-fold. On the other hand, PMA did
not change the stability of the NOS III mRNA. These data indicate that
stimulation of PKC, PKC, or both by active phorbol esters
represents an efficacious pathway activating the human NOS III promoter
in human endothelium.
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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