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J Biol Chem, Vol. 275, Issue 5, 3075-3080, February 4, 2000
From the We have previously shown that the
immunosuppressant cyclosporine A (CsA) increases the activity, the
protein level, and the steady-state levels of the mRNA of the
endothelial nitric-oxide synthase (eNOS) gene in bovine aortic
endothelial cells (BAEC). We have now investigated the mechanisms
responsible for these effects. Preincubation with an inhibitor of RNA
polymerase II abolished CsA-induced eNOS up-regulation.
Nuclear run-on experiments demonstrated a 1.6-fold increase in the
induction of eNOS gene by CsA. In agreement with these
results, transient transfections showed that CsA augmented the
transactivation of the eNOS promoter. Electrophoretic
mobility shift assays showed an increase in the activator protein-1
(AP-1) DNA binding activity in BAEC treated with CsA. An increase in
the level of c-fos mRNA and in the nuclear content of
c-Fos protein was detected in BAEC treated with CsA. Site-directed
mutagenesis of the AP-1 cis-regulatory element in the
context of the human eNOS promoter resulted in the
abrogation of the induction mediated by CsA. Hence, up-regulation of
eNOS mRNA by CsA is a transcriptional phenomenon
involving the proximal AP-1 site in the 5'-regulatory region of the
human eNOS gene. Furthermore, our data exemplify how
immunosuppressive drugs may result in the regulation of specific genes
involved in the homeostasis of endothelial function, such as
eNOS.
Transcriptional Induction of Endothelial Nitric Oxide Gene by
Cyclosporine A
A ROLE FOR ACTIVATOR PROTEIN-1*
§¶,, and§
Centro de Investigaciones Biológicas,
Consejo Superior de Investigaciones Científicas and the
§ Instituto Reina Sofía de Investigaciones
Nefrológicas, 28006 Madrid, Spain
*
This work was supported by Grant SAF-97-0035 from the
Comisión Interministerial de Ciencia y Tecnologia, Grant
BMH4-CT96-0979 from European Union Program BIOMED-2, and Grant
08.4/0032/1998 from Comunidad Autonoma de Madrid.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Centro de
Investigaciones Biológicas, c/Velázquez 144, 28006 Madrid,
Spain. Tel.: 34-91-5644562 (ext. 4302); Fax: 34-91-5627518; E-mail:
slamas@cib.csic.es.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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