Central role for ornithine decarboxylase in β-adrenoceptor mediated hypertrophy

Objective: TGF-β stimulation of cardiac myocytes induces a hypertrophic responsiveness to β-adrenoceptor stimulation. This study investigates whether this β-adrenoceptor mediated effect depends on induction of ornithine decarboxylase (ODC). Methods: Isolated adult ventricular cardiomyocytes from rats were used as an experimental model. Cells were either cultured in 20% (v/v) FCS to activate autocrine released TGF-β or used without pre-treatment. The hypertrophic response was characterized by an increased 14C-phenylalanine incorporation, RNA and protein mass or by an increased expression of atrionatriurectic factor and ODC. The results on cell cultures were compared to those achieved by isoprenaline perfused mice hearts from transgenic mice overexpressing TGF-β1. Results: ODC activity and expression increased within 2 h in TGF-β1 pre-treated cells under isoprenaline. In the presence of ODC inhibitors (α-methylornithine or difluoromethylornithine) this increase remained absent and the increases in 14C-phenylalanine incorporation, protein and RNA mass under isoprenaline were abolished. In cells not exposed to TGF-β no induction of ODC was observed. Isoprenaline also induced ODC in isolated perfused ventricles from transgenic mice overexpressing TGF-β1, but not in ventricles from their nontransgenic counterparts. Conclusions: This study shows first, a pivotal role for ODC induction in the hypertrophic response of cardiomyocytes to β-adrenoceptor stimulation and second, that ODC induction in vivo and in vitro requires pre-treatment of cardiomyocytes with TGF-β. It is concluded that TGF-β induces a hypertrophic responsiveness to β-adrenoceptor stimulation that is characterized by ODC induction.