| First Author | Hill C | Year | 2013 |
| Journal | Cardiovasc Res | Volume | 99 |
| Issue | 1 | Pages | 121-8 |
| PubMed ID | 23612584 | Mgi Jnum | J:211393 |
| Mgi Id | MGI:5574579 | Doi | 10.1093/cvr/cvt094 |
| Citation | Hill C, et al. (2013) Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction. Cardiovasc Res 99(1):121-8 |
| abstractText | 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 beta-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 TGFbeta1. 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. |
