title: Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction.
abstract: OBJECTIVE
  Expression and activity of the transcription factor AP-1 are enhanced during cardiac remodelling and heart failure progression. In order to test if AP-1 inhibition may limit processes contributing to cardiac remodelling, ventricular cardiomyocytes of mice with cardiac overexpression of the AP-1 inhibitor JDP2 were analysed under stimulation of hypertrophy, apoptosis, or contractile function.
  
  
  RESULTS
  Three models of JDP2 overexpressing mice were analysed: JDP2 was overexpressed either life-long, for 7 weeks, or 1 week. Then cardiomyocytes were isolated and stimulated with β-adrenoceptor agonist isoprenaline (ISO, 50 nM). This enhanced cross-sectional area and the rate of protein synthesis in WT but not in JDP2 overexpressing cardiomyocytes. To induce apoptosis, cardiomyocytes were stimulated with 3 ng/mL TGFβ1. Again, JDP2 overexpression prevented apoptosis induction compared with WT cells. Determination of contractile function under electrical stimulation at 2 Hz revealed enhancement of cell shortening, and contraction and relaxation velocities under increasing ISO concentrations (0.3-30 nM) in WT cells. This inotropic effect was abrogated in JDP2 overexpression cells. Responsiveness to increased extracellular calcium concentrations was also impaired in JDP2 overexpressing cardiomyocytes. Simultaneously, a reduction of SERCA expression was found in JDP2 mice.
  
  
  CONCLUSIONS
  A central role of AP-1 in the induction of hypertrophy and apoptosis in cardiomyocytes is demonstrated. Besides these protective effects of AP-1 inhibition on factors of cardiac remodelling, AP-1-inhibition impairs contractile function. Therefore, AP-1 acts as a double-edged sword that mediates mal-adaptive cardiac remodelling, but is required for maintaining a proper contractile function of cardiomyocytes.
authors.affiliation: Physiologisches Institut, Justus-Liebig-Universität Giessen, Aulweg 129, 35392 Gießen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hill
authors.forename: Alona
authors.initials: A
authors.lastname: Würfel
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Heger
authors.forename: Bettina
authors.initials: B
authors.lastname: Meyering
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Schlüter
authors.forename: Martin
authors.initials: M
authors.lastname: Weber
authors.forename: Peter
authors.initials: P
authors.lastname: Ferdinandy
authors.forename: Ami
authors.initials: A
authors.lastname: Aronheim
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Gerhild
authors.initials: G
authors.lastname: Euler
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: D000318:Adrenergic beta-Agonists; C491386:Jundp2 protein, mouse; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1
keywords: Apoptosis; Cardiac; Contractile function; Hypertrophy; Remodeling; Transcription factor AP-1