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JunD attenuates phenylephrine-mediated cardiomyocyte hypertrophy by negatively regulating AP-1 transcriptional activity.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2006 Jul 01; Vol. 71 (1), pp. 108-17. Date of Electronic Publication: 2006 Mar 07. - Publication Year :
- 2006
-
Abstract
- 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).<br />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.<br />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.<br />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.
- Subjects :
- Adrenergic alpha-Agonists pharmacology
Animals
Atrial Natriuretic Factor genetics
Atrial Natriuretic Factor metabolism
DNA metabolism
Electrophoretic Mobility Shift Assay
Phenylephrine pharmacology
Proto-Oncogene Proteins c-fos genetics
Proto-Oncogene Proteins c-fos metabolism
Proto-Oncogene Proteins c-jun genetics
RNA, Messenger analysis
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha metabolism
Stimulation, Chemical
Transcription Factor AP-1 genetics
Transfection methods
Cardiomegaly metabolism
Myocytes, Cardiac metabolism
Proto-Oncogene Proteins c-jun metabolism
Transcription Factor AP-1 metabolism
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0008-6363
- Volume :
- 71
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 16690042
- Full Text :
- https://doi.org/10.1016/j.cardiores.2006.02.032