JunD attenuates phenylephrine-mediated cardiomyocyte hypertrophy by negatively regulating AP-1 transcriptional activity

被引:31
作者
Hilfiker-Kleiner, Denise
Hilfiker, Andres
Castellazzi, Marc
Wollert, Kai C.
Trautwein, Christian
Schunkert, Heribert
Drexler, Helmut
机构
[1] Hannover Med Sch, Dept Cardiol, D-30625 Hannover, Germany
[2] Hannover Med Sch, Dept Angiol, D-30625 Hannover, Germany
[3] Hannover Med Sch, D-3000 Hannover, Germany
[4] INSERM, U758, IFR128, F-69008 Lyon, France
[5] Univ Klinikum, Rhein Westfal TH Aachen, Aachen, Germany
[6] Med Univ Lubeck, D-23538 Lubeck, Germany
关键词
adrenergic agonists; hypertrophy; signal transduction; cardiomyocyte;
D O I
10.1016/j.cardiores.2006.02.032
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 [H-3]-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. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:108 / 117
页数:10
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