Central role for ornithine decarboxylase in beta-adrenoceptor mediated hypertrophy.

OBJECTIVE TGF-beta stimulation of cardiac myocytes induces a hypertrophic responsiveness to beta-adrenoceptor stimulation. This study investigates whether this beta-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-beta 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-beta 1. RESULTS ODC activity and expression increased within 2 h in TGF-beta 1 pre-treated cells under isoprenaline. In the presence of ODC inhibitors (alpha-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-beta no induction of ODC was observed. Isoprenaline also induced ODC in isolated perfused ventricles from transgenic mice overexpressing TGF-beta 1, 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 beta-adrenoceptor stimulation and second, that ODC induction in vivo and in vitro requires pre-treatment of cardiomyocytes with TGF-beta. It is concluded that TGF-beta induces a hypertrophic responsiveness to beta-adrenoceptor stimulation that is characterized by ODC induction.