Abstract 3205: Growth Differentiation Factor-15 Acts Anti-apoptotic and Pro-hypertrophic in Adult Cardiomyocytes
Aims: 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, in the present study we investigated the effects of GDF15 on induction of hypertrophy and apoptosis in ventricular cardiomyocytes.
Methods and Results: Dose-response analysis of SMAD-binding affinity under stimulation with GDF15 revealed a maximal activation of SMADs, as the classical transcription factors in GDF15 signaling, by addition of 3 ng/ml GDF15 to cardiomyocytes. Under these conditions enhancement of SMAD1,5,8 phosphorylation, as another parameter of SMAD activation, was seen. At the same concentration, GDF15 enhanced hypertrophic growth as determined by an increase in cell size by 27±5 % and rate of protein synthesis by 47±15 %. Inhibition of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished this growth effect. Furthermore, specific inhibitors of PI3K (10 μM LY290042 or 10 nM wortmannin) or ERK (10 μM PD98059) also blocked GDF15 induced hypertrophy. Activation of ERK was determined in western blots and revealed a sustained induction under GDF15 over at least 4 hours. Apoptosis was stimulated by three different agents, 100 nM angiotensinII, 1ng/ml TGFβ1, or the NO-donor SNAP (100 μM) in adult cardiomyocytes of rat. Under all conditions, GDF15 (3 ng/ml) blocked apoptosis induction. This protective effect was mediated by the transcription factor SMAD, since scavenging of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the protection.
Conclusions: 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 SMAD. Thus, GDF15 may influence cardiac remodeling via two different mechanisms, apoptosis protection and induction of hypertrophy.