Growth differentiation factor 15 (GDF15) is induced during heart failure development, and may influence different processes in cardiac remodeling. While its anti-apoptotic action under conditions of ischemia-reperfusion have been shown, it remained unclear if this is a broadly protective effect applicable to other apoptotic stimuli. Furthermore, effects on cardiac hypertrophy remained obscure. Therefore, we investigated the effects of GDF15 on induction of hypertrophy and apoptosis in ventricular cardiomyocytes. GDF15 (3 ng/ml) enhanced hypertrophic growth of cardiomyocytes as determined by an increase in cell size by 27 +/- 5% and rate of protein synthesis by 47 +/- 15%. In addition, a time and dose-dependent increase in SMAD-binding affinity was found, as well as enhanced phosphorylation of R-SMAD1. Inhibition of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the hypertrophic growth effect. Specific inhibitors of PI3K (10 microM LY290042 or 10 nM wortmannin) or ERK (10 microM PD98059) also blocked GDF15-induced hypertrophy and SMAD activation. Apoptosis induction by three different agents, 100 nM angiotensin II, 1 ng/ml TGFbeta(1), or the NO-donor SNAP (100 microM) was blocked by addition of GDF15 (3 ng/ml). Scavenging of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the anti-apoptotic effect of GDF15. In conclusion, GDF15 protects ventricular cardiomyocytes against different apoptotic stimuli and enhances hypertrophic growth. Hypertrophic signaling is thereby mediated via the kinases PI3K and ERK and the transcription factor R-SMAD1. Thus, GDF15 may influence cardiac remodeling via two different mechanisms, apoptosis protection and induction of hypertrophy.

Our data demonstrate that the pro-vasculogenic effects of PDGF-BB are mediated by Ca(2+)-induced ROS generation, resulting in the activation of an ERK1,2-mediated signal transduction cascade.

Myocardial infarction is a prevailing cause of death in industrial countries. In spite of the good opportunities we have nowadays in interventional cardiology to reopen the clotted coronary arteries for reperfusion of ischemic areas, post-infarct remodeling emerges and contributes to unfavorable structural conversion processes in the myocardium, finally resulting in heart failure. The growth factor TGFβ is upregulated during these processes. In this review, an overview on the functional role of TGFβ signaling in the process of cardiac remodeling is given, as it can influence apoptosis, fibrosis and hypertrophy thereby predominantly aggravating ischemia/reperfusion injury.

Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.

Elevations in angiotensin II (AngII) and transforming growth factor (TGF-beta1) levels are often found under conditions leading to progression of heart failure. From several studies, it is evident that AngII enhances TGF-beta1 expression via activator protein 1 (AP-1) activation, and that this pathway is involved in hypertrophic growth of the heart muscle and in the development of cardiac fibrosis. We now continued characterization of the signaling pathway stimulated by AngII in ventricular cardiomyocytes of rat and analyzed if the enhancement of TGF-beta1 expression by AngII may also contribute to apoptosis induction, which is another predictor of heart failure progression. Stimulation of cardiomyocytes with 100 nM AngII for 2 h activated the transcription factors AP-1 and GATA by 68.6+/-23.9 or 70.7+/-9.8%. Induction of both factors was mediated by p38 mitogen-activated protein kinase (MAPK) because it was totally blocked using a specific inhibitor of the kinase (SB202190). When GATA was inhibited by transformation of cardiomyocytes with decoy oligonucleotides, AngII could not enhance TGF-beta1 expression. This inhibition was observed on the mRNA level in real-time polymerase chain reaction and on the protein level in Western blots. As a consequence, upon AngII stimulation for 24 h, release of TGF-beta1 from cardiomyocytes was also reduced from 240.5+/-50.4 to 130.5+/-22.1% (p<0.05). In contrast to the early induction of GATA and AP-1, the transcription factor similar to mothers against decapentaplegic homolog (SMAD) was induced by AngII after 24 h. This stimulation was dependent on TGF-beta1 because it was blocked by antibodies specific for TGF-beta1. Twenty-four hours after AngII addition, the number of apoptotic cardiomyocytes increased by 6.5+/-1.2%, and this apoptosis induction was blocked when SMAD activity was inhibited by transformation of cardiomyocytes with SMAD decoy oligonucleotides. In conclusion, the transcription factors AP-1 and GATA are activated by p38 MAPK upon AngII stimulation, and both are needed to enhance TGF-beta1 expression in ventricular cardiomyocytes. TGF-beta1 acts in an autocrine loop on the cells to induce apoptosis via SMAD signaling. Thus, the often-found correlation between AngII, TGF-beta1, AP-1, and SMAD in pathogenesis of heart disease reflects the proapoptotic signaling pathway induced by AngII in cardiomyocytes.