Document Detail


JunD attenuates phenylephrine-mediated cardiomyocyte hypertrophy by negatively regulating AP-1 transcriptional activity.
MedLine Citation:
PMID:  16690042     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Mice deficient for the AP-1 transcription factor JunD, the only Jun protein constitutively expressed and clearly detectable in the mammalian heart, develop enhanced cardiac hypertrophy in response to chronic pressure overload. Catecholamines inducing alpha-adrenergic receptor-mediated signaling have been implicated in the neurohumoral response to pressure overload and the development of left ventricular hypertrophy. In the present study we analyzed the mechanistic role of JunD in cardiomyocyte hypertrophy in vitro in response to alpha-adrenergic agonist phenylephrine (PE). METHODS: Cardiomyocytes were isolated from 1- to 3-day-old rats and transfected with adenoviruses expressing LacZ or wild-type JunD, or with expression vectors encoding LacZ, wild-type JunD, mutated JunD forming only JunD homodimers (JunDeb1), mutated JunD lacking the JNK site (JunD-Delta 162), or c-Jun. After stimulation with PE (10(-5) mol/L), hypertrophic growth of cardiomyocytes (cross-sectional area and [3H]-leucine incorporation) and mRNA expression of JunD, c-Jun, c-Fos, and atrial natriuretic peptide (ANP) were analyzed. Transcriptional activation was determined by luciferase activity in cardiomyocytes transfected with AP-1 or ANP luciferase reporter plasmids. Gel shift assays with an AP-1 consensus oligonucleotide were performed to analyze AP-1 DNA binding activities. RESULTS: PE augmented mRNA levels of c-Jun and c-Fos, but decreased JunD transcript levels. Adenoviral over-expression of wild-type JunD blunted PE-induced hypertrophic growth and expression of ANP mRNA. Over-expression of JunD in cardiomyocytes caused enhanced AP-1 protein-DNA binding, without increasing the transcriptional response from AP-1 or ANP luciferase reporter plasmids at baseline or upon PE stimulation. Moreover, over-expression of JunDeb1 attenuated transcription from AP-1 or ANP luciferase reporter plasmids and blunted c-Jun-mediated acceleration of AP-1 transcriptional activity at baseline and in response to PE. CONCLUSIONS: Our observations establish a novel role for JunD as a negative regulator of cardiomyocyte hypertrophy in response to hypertrophic stimuli by inhibiting AP-1 transcriptional activity.
Authors:
Denise Hilfiker-Kleiner; Andres Hilfiker; Marc Castellazzi; Kai C Wollert; Christian Trautwein; Heribert Schunkert; Helmut Drexler
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-03-07
Journal Detail:
Title:  Cardiovascular research     Volume:  71     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-06-13     Completed Date:  2007-03-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  108-17     Citation Subset:  IM    
Affiliation:
Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. hilfiker.denise@mh-hannover.de
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MeSH Terms
Descriptor/Qualifier:
Adrenergic alpha-Agonists / pharmacology
Animals
Atrial Natriuretic Factor / genetics,  metabolism
Cardiomegaly / metabolism*
DNA / metabolism
Electrophoretic Mobility Shift Assay
Myocytes, Cardiac / metabolism*
Phenylephrine / pharmacology
Proto-Oncogene Proteins c-fos / genetics,  metabolism
Proto-Oncogene Proteins c-jun / genetics,  metabolism*
RNA, Messenger / analysis
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha / metabolism
Stimulation, Chemical
Transcription Factor AP-1 / genetics,  metabolism*
Transcription, Genetic*
Transfection / methods
Chemical
Reg. No./Substance:
0/Adrenergic alpha-Agonists; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Receptors, Adrenergic, alpha; 0/Transcription Factor AP-1; 59-42-7/Phenylephrine; 85637-73-6/Atrial Natriuretic Factor; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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