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J. Biol. Chem., Vol. 276, Issue 37, 34983-34989, September 14, 2001
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From the Department of Cardiovascular Medicine, Graduate School of
Medicine, Kyoto University, Kyoto, 606-8507 Japan
Increases in the expression of endothelin-1
(ET-1) in cardiac myocytes play a critical role in the development of
heart failure in vivo. Whereas norepinephrine (NE) is a
potent inducer of ET-1 expression in cardiac myocytes, the signaling
pathways that link NE to inducible cardiac ET-1 expression are unknown.
Adrenergic stimulation results in an increase in intracellular calcium
levels, which in turn activates calcineurin. Here, we have shown that stimulation with NE markedly increased the expression of the
ET-1 gene in primary cardiac myocytes from neonatal rats.
This increase was severely attenuated by a
Calcineurin-GATA4 Pathway Is Involved in
-Adrenergic Agonist-responsive Endothelin-1 Transcription in
Cardiac Myocytes*
,
-adrenergic antagonist,
metoprolol, but not by an 
-adrenergic antagonist, prazosin.
Consistent with these data, the -adrenergic agonist isoproterenol
(ISO) activated the rat ET-1 promoter activity to an extent
that was similar to NE. The ISO-stimulated increase in promoter
activity was significantly inhibited by a Ca2+-antagonist,
nifedipine, and an immunosuppressant, cyclosporin A, which blocks
calcineurin. Mutation analysis indicated that the GATA4 binding site is
required for ISO-responsive ET-1 transcription. Stimulation with ISO
enhanced the interaction between NFATc and GATA4 in cardiac myocytes.
Consistent with this interaction, overexpression of GATA4 and NFATc
synergistically activated the ET-1 promoter. These
findings demonstrate that NE-stimulated ET-1 expression in cardiac
myocytes is mediated predominantly via a -adrenergic pathway, and
that calcium-activated calcineurin-GATA4 plays a role in this process.
*
This work was supported in part by grants from the Ministry
of Education, Science and Culture of Japan (to K. H.).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: Dept. of
Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan. Tel.: 81-75-751-3190; Fax: 81-75-751-3203; E-mail:
koj@kuhp.kyoto-u.ac.jp.
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