Central role for ornithine decarboxylase in beta-adrenoceptor mediated hypertrophy

Objective: TGF-P stimulation of cardiac myocytes induces a hypertrophic res ponsiveness to beta-adrenoceptor stimulation. This study investigates wheth er this beta-adrenoceptor mediated effect depends on induction of ornithine decarboxylase (ODC). Methods: Isolated adult ventricular cardiomyocytes fr om rats were used as an experimental model. Cells were either cultured in 2 0% (v/v) FCS to activate autocrine released TGF-beta or used without pre-tr eatment. The hypertrophic response was characterized by an increased C-14-p henylalanine incorporation, RNA and protein mass or by an increased express ion of atrionatriurectic factor and ODC. The results on cell cultures were compared to those achieved by isoprenaline perfused mice hearts from transg enic mice overexpressing TCF-beta(1). Results: ODC activity and expression increased within 2 h in TGF-beta(1) pre-treated cells under isoprenaline. I n the presence of ODC inhibitors (alpha-methylornithine or difluoromethylor nithine) this increase remained absent and the increases in C-14-phenylalan ine incorporation, protein and RNA mass under isoprenaline were abolished. In cells not exposed to TGF-beta no induction of ODC was observed. Isoprena line 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 i nduction in the hypertrophic response of cardiomyocytes to beta-adrenocepto r stimulation and second, that ODC induction in vivo and in vitro requires pre-treatment of cardiomyocytes with TGF-beta. It is concluded that TGF-bet a induces a hypertrophic responsiveness to beta-adrenoceptor stimulation th at is characterized by ODC induction. (C) 2000 Elsevier Science B.V. All ri ghts reserved.