Aims:

Cardiac remodeling is related to heart failure progression. Expression and activity of the transcription factor AP-1 is enhanced during these processes and may thus contribute to heart failure development. In order to analyse effects of AP-1 inhibition on cardiac remodeling, ventricular cardiomyocytes of transgenic mice with cardiac overexpression of the AP-1 inhibitor JDP2 were analysed on parameters of hypertrophic growth, apoptosis and contractile function.

Methods and Results:

Ventricular cardiomyocytes were isolated from 8 weeks old transgenic and WT mice. First, effect of β-adrenergic stimulation with isoprenaline (50 nM) on hypertrophic growth was analysed. This enhanced cross sectional area and the rate of protein synthesis within 24 h in WT but not in JDP2 overexpressing cardiomyocytes. Contractile function of cardiomyocytes was investigated under electrical stimulation at 2 Hz in presence of increasing concentrations of ISO (0.3 to 30 nM). While in WT cells, cell shortening as well as contraction and relaxation velocities under increasing ISO concentrations were enhanced, this inotropic effect was abrogated in JDP2 overexpression cells. At the same time, a reduction of SERCA mRNA expression was found in JDP2 overexpressing cardiomyocytes. As determined by real time PCR, β1- and β2-adrenoceptor levels were the same in JDP2 and WT. Thus, abrogation of β-adrenergic responses must lie downstream of receptor activation. Furthermore, influence of AP-1 inhibition on TGFβ1-induced apoptosis was analysed. To be sure that TGFβ/SMAD signalling is not influenced by JDP2 overexpression per se, mRNA expression of TGFβ₁, SMAD2 and SMAD3 in left ventricles of WT and JDP2 mice were compared. Real time PCR revealed no overt changes in expression of TGFβ₁-, SMAD2- and SMAD3-mRNA. Stimulation with 3 ng/ml TGFβ₁ for 4.5 h enhanced apoptosis in WT but not in JDP2 overexpressing cardiomyocytes.

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 negatively influences cardiomyocytes by impairment of contractile function. Thus, when thinking about development of AP-1 inhibitors for prevention of cardiac remodelling care should be taken.