Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction

Cardiovasc Res. 2013 Jul 1;99(1):121-8. doi: 10.1093/cvr/cvt094. Epub 2013 Apr 23.


Aims: 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.

Methods and 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.

Conclusion: 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.

Keywords: Apoptosis; Cardiac; Contractile function; Hypertrophy; Remodeling; Transcription factor AP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Apoptosis* / drug effects
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomegaly / prevention & control*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardial Contraction
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction* / drug effects
  • Time Factors
  • Transcription Factor AP-1 / metabolism*
  • Transforming Growth Factor beta1 / metabolism
  • Up-Regulation
  • Ventricular Remodeling


  • Adrenergic beta-Agonists
  • Jundp2 protein, mouse
  • Repressor Proteins
  • Transcription Factor AP-1
  • Transforming Growth Factor beta1