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J Biol Chem, Vol. 275, Issue 18, 13721-13726, May 5, 2000
From the Department of Cardiovascular Medicine, Graduate School of
Medicine, Kyoto University, Kyoto 606-8507, Japan
The expression of endothelin-1 (ET-1) in cardiac
myocytes is markedly induced during the development of heart failure
in vivo and by stimulation with the
Phosphorylation of GATA-4 Is Involved in
1-Adrenergic Agonist-responsive Transcription of the
Endothelin-1 Gene in Cardiac Myocytes*
,
1-adrenergic agonist phenylephrine in culture. Although
recent studies have suggested a role for cardiac-specific zinc finger
GATA factors in the transcriptional pathways that modulate cardiac
hypertrophy, it is unknown whether these factors are also involved in
cardiac ET-1 transcription and if so, how these factors are modulated
during this process. Using transient transfection assays in primary
cardiac myocytes from neonatal rats, we show here that the GATA element
in the rat ET-1 promoter was required for phenylephrine-stimulated ET-1 transcription. Cardiac GATA-4 bound the ET-1 GATA element and activated
the ET-1 promoter in a sequence-specific manner. Stimulation by
phenylephrine caused serine phosphorylation of GATA-4 and increased its
ability to bind the ET-1 GATA element. Inhibition of the
extracellularly responsive kinase cascade with PD098059 blocked the
phenylephrine-induced increase in the DNA binding ability and the
phosphorylation of GATA-4. These findings demonstrate that serine
phosphorylation of GATA-4 is involved in 1-adrenergic
agonist-responsive transcription of the ET-1 gene in cardiac myocytes
and that extracellularly responsive kinase 1/2 activation plays a role
upstream of GATA-4.
*
This work was supported in part by grants from the Suzuken
Memorial Foundation, the Mochida Memorial Foundation for Medical and
Pharmaceutical Research, the Yamanouchi Foundation for Research on
Metabolic Disorders, and 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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