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Published on: June 3, 2018
JunD attenuates phenylephrine-mediated cardiomyocyte hypertrophy by negatively regulating AP-1 transcriptional
Denise Hilfiker-Kleiner1, Andres Hilfiker, Marc Castellazzi
1Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. hilfiker.denise@mh-hannover.de
Insights
JunD acts as a crucial negative regulator in cardiac hypertrophy. This study shows JunD inhibits AP-1 transcriptional activity, preventing excessive cardiomyocyte growth in response to hypertrophic stimuli.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Transcription Factor Regulation
Background:
- JunD is the only constitutively expressed Jun protein in the mammalian heart.
- Mice lacking JunD exhibit enhanced cardiac hypertrophy under pressure overload.
- Catecholamines and alpha-adrenergic signaling contribute to left ventricular hypertrophy.
Purpose of the Study:
- To investigate the role of JunD in cardiomyocyte hypertrophy.
- To analyze JunD's mechanism in response to alpha-adrenergic stimulation (phenylephrine).
Main Methods:
- Isolated rat cardiomyocytes were transfected with JunD or control vectors.
- Cells were stimulated with phenylephrine (PE).
- Assessed hypertrophic growth, mRNA expression (JunD, c-Jun, c-Fos, ANP), and AP-1 transcriptional activity via reporter plasmids and gel shift assays.
Main Results:
- PE increased c-Jun and c-Fos mRNA but decreased JunD mRNA.
- Overexpression of JunD reduced PE-induced hypertrophy and ANP mRNA levels.
- JunD overexpression enhanced AP-1 DNA binding but not transcriptional activity; JunDeb1 mutants impaired AP-1 activity.
Conclusions:
- JunD functions as a novel negative regulator of cardiomyocyte hypertrophy.
- JunD inhibits AP-1 transcriptional activity, thereby limiting cardiac hypertrophy in response to stimuli.
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.
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