GDF15 is a member of the TGFb superfamily that is up-regulated in the heart after ischemic conditions. Unlike other family members GDF15 acts anti-apoptotic. This suggests protective properties for the heart. To analyze which role GDF15 plays in hypertrophic growth cardiomyocytes of adult rat (CM) were incubated with GDF15 (3ng/ml) over 24 h. Simular to a- adrenoceptor agonist phenylephrine (PE, 10 mM) GDF15 enhanced cross sectional area (CSA) and increased protein synthesis rate that can be blocked with inhibitors of the PI3- kinase. In contrast to PE GDF15-stimulated hypertrophy could be blocked with MAPK-inhibitor PD9805 (10 mM). Since the transcription factors SMAD are the classical signal molecules of the TGFb super family, we analyzed the role of SMADs in the development of hypertrophy. Stimulation with GDF15 enlarged SMAD binding activity in EMSAs, whereas with PE SMAD binding activity did not increase. Transformation of CM with SMAD decoy oligonucleotides, which intracellular scavenge SMAD proteins, decreased GDF15 induced protein synthesis. Conclusion: GDF15 initiates hypertrophic growth in adult ventricular cardiomyocytes of rat. Like the classical a-adrenergic signalling this pathway of hypertrophy induction is mediated via PI3-kinase. In contrast to the a-adrenergic pathway MAP-Kinase ERK and the transcription factor SMAD take part in the hypertrophy induction stimulated by GDF15.