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J. Biol. Chem., Vol. 277, Issue 50, 48617-48626, December 13, 2002
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From the The calcium-activated phosphatase calcineurin has
been implicated as a critical intracellular signal transducer of
cardiomyocyte hypertrophy. Although previous data suggested the nuclear
factor of activated T-cells (NFAT) as its sole transcriptional
effector, the absolute requirement of NFAT as a mediator of calcineurin signaling has not been examined in the heart. We therefore investigated the expression and activation profile of NFAT genes in the heart. Four
members (NFATc1-c4) are expressed in cardiomyocytes, elicit nuclear
translocation upon calcineurin activation, and are able to drive
transactivation of cardiac promoter luciferase constructs. To define
the necessary function of NFAT factors as hypertrophic transducers, a
dominant negative NFAT construct was created, encompassing part of the
N-terminal region of NFATc4 containing a conserved calcineurin-binding
motif. Cotransfection of this construct dose-dependently abrogated promoter activation, irrespective of the NFAT isoform used,
whereas a control construct with the calcineurin-binding motif mutated
displayed no such effects. Adenoviral gene transfer of dominant
negative NFAT rendered cardiomyocytes resistant toward all aspects of
calcineurin or agonist-induced cardiomyocyte hypertrophy, whereas
adenoviral gene transfer of the control construct had no discernable
effect on these parameters. These results indicate that multiple NFAT
isoforms are expressed in cardiomyocytes where they function as
necessary transducers of calcineurin in facilitating cardiomyocyte hypertrophy.
Requirement of Nuclear Factor of Activated T-cells in
Calcineurin-mediated Cardiomyocyte Hypertrophy*
,§,,,
Department of Cardiology, Cardiovascular
Research Institute Maastricht, University Hospital, P. Debyelaan
25, Maastricht, LB 6202 AZ, the Netherlands, the
§ Interuniversitary Cardiology Institute Netherlands,
3501 D.G. Utrecht, the Netherlands, and the ¶ Division of
Molecular Cardiovascular Biology, Department of Pediatrics, Children's
Hospital Medical Center, Cincinnati, Ohio 45229
*
This work was supported by the Netherlands Heart Foundation
(Grants NHS 99-114 and NHS 2000-160) and the Interuniversitary Cardiology Institute Netherlands (to P. A. D); by National Institutes of Health Grants HL60562 and HL07382 and a Scholar Award from the Pew
Foundation (to J. D. M.); and an American Heart Postdoctoral Fellowship (Ohio Valley Affiliate), a Young Investigator's Award in
Cardiology from the Bekales Foundation, and Grant NWO 902-16-275 from
the Netherlands Foundation for Scientific Research (to L. J. D. W.).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
Cardiology, University Hospital Maastricht, P. Debeyelaan 25, P. O.
Box 5800, Maastricht 6202 AZ, The Netherlands. Tel.: 31-43-388-2949; Fax: 31-43-387-5104; E-mail: leon.dewindt@cardio.unimaas.nl.
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