Myocardial Cells

Since transforming growth factor-f3l (TGF-,31) has been recently shown to be expressed in the heart by mechanical stretch and ischemic injury, we examined the modulation of c-fos mRNA expression and amino acid uptake by TGF-,3, in rat myocardial cells. Pretreatment with TGF-j31 potentiated norepinephrine (NE)-induced and stretch-induced (+ 10% and +20% elongation, for 30 minutes) c-fos mRNA expression by 2.2-fold, whereas TGF-,l1 alone did not induce c-fos mRNA expression in Northern blot analysis. NE-induced [14C]phenylalanine uptake was also potentiated with TGF-3,1 pretreatment. The effect of TGF-j31 on the NE action was not blocked by propranolol but by prazosin. The protein kinase C activators (12-O-tetradecanoylphorbol 13-acetate [TPA], phorbol T he cellular homologue of the oncogene of two mouse osteosarcoma viruses, c-fos,' is implicated in the transcriptional activation of phorbol-inducible genes by binding of the Fos/Jun heterodimer complex to a consensus AP-1 site in the promoter region of these genes.2 4 Studies using antisense constructs have shown that c-fos induction is required for cell proliferation and the onset of DNA synthesis after growth factor stimulation.5,6 c-fos is rarely detected in the cardiac muscle of the normal adult rat or mouse. However, hemodynamic stress and a,-adrenergic agonists, both of which are known to produce cardiac hypertrophy, rapidly provoke c-fos expression through protein kinase C (PKC) activation in ventricular myocardium.7-9 Thus, c-fos that is induced at the early stage of various stimulations in myocardial cells may play an important role in cardiac hypertrophy. Transforming growth factor-f,1 (TGF-f31), a 25 000-D homodimeric molecule originally described in transformed cells, is known to be a multifunctional peptide. mRNA of TGF-,31 can be detected in a wide range of tissues, and most cells have high-affinity receptors for TGF-/31, indicating that this molecule has a broad spectrum of tissue functions.10-12 TGF-3,1 has been shown to be present in both developing and adult myocardial cells and also in the extracellular matrix of the adult heart.13-15 Recent studies have shown that Received August 5, 1993; accepted March 1, 1994. From The First Department of Internal Medicine, Kobe University School of Medicine (Japan). Correspondence to Mitsuhiro Yokoyama, MD, The First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650, Japan. C 1994 American Heart Association, Inc. 12,13-dibutyrate, and 1-oleyl-2-acetyl-rac-glycerol) induced c-fos mRNA expression, which was also potentiated by TGF/. Cycloheximide (protein synthesis inhibitor) could not suppress the TGF-f31 actions. In nonmuscle cells, TGF-131 modified neither adrenergic nor TPA-induced c-fos mRNA expression. These data suggested that TGF-,81 potentiated the c-fos mRNA expression and amino acid incorporation by modification of the a1-adrenergic and stretch-activated protein kinase C pathway. This mechanism did not require protein synthesis. (Circ Res. 1994;75:8-14.)