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Vol. 57, Issue 3, 427-435, March 2000
Department of Pharmacology, Johannes Gutenberg University, Mainz,
Germany
In human umbilical vein endothelial cells and in human umbilical vein
endothelial cell-derived EA.hy 926 cells, staurosporine (Stsp) and its
glycosidic indolocarbazole analogs 7-hydroxystaurosporine (UCN-01)
and 4'-N-benzoyl staurosporine (CGP 41251) enhanced
nitric-oxide synthase (NOS) III mRNA expression (analyzed by RNase
protection assay), protein expression (determined by Western blot), and
activity [measured by rat fetal lung fibroblast (RFL-6) reporter cell
assay] in a concentration- and time-dependent manner. In
contrast, the bisindolylmaleimide analogs GF 109203X, Ro 31-8220 and
Gö 6983 had no effect on NOS III expression, and Gö 6976, a
methyl- and cyanoalkyl-substituted nonglycosidic indolocarbazole
derivative of Stsp, even reduced NOS III expression in a
concentration-dependent fashion. The up-regulation of NOS III
expression by Stsp and analogs appears to be a transcriptional event
because Stsp, 7-hydroxystaurosporine, and CGP 41251 enhanced the
activity of a 1.6-kb human NOS III promoter fragment transiently
transfected into EA.hy 926 endothelial cells. Stsp and analogs did not
affect the stability of the NOS III mRNA. Stsp is known as a potent
protein kinase (PK) inhibitor. Data obtained with other kinase
inhibitors (and stimulators) indicated, however, that the effect of
Stsp and analogs on NOS III expression was unrelated to the activities
of PKC, PKA, PKG, or tyrosine kinase(s). Stsp analogs such as CGP 41251 also counteracted the NOS III mRNA-decreasing effect of tumor necrosis
factor-
. These findings demonstrate that Stsp analogs represent a
new class of compounds positively interacting with the transcription of
the endothelial NOS III gene. Such compounds may prove useful in the prophylaxis and therapy of vascular disease.
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