Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes

• Published in: The Journal of clinical investigation Vol. 94; no. 4; pp. 1470 - 1476
• Main Authors: Takahashi, N, Calderone, A, Izzo, Jr, N J, Mäki, T M, Marsh, J D, Colucci, W S
• Format: Journal Article
• Language: English
• Published: United States 01.10.1994
• Subjects: Animals; Animals, Newborn; Aorta, Abdominal; Atrial Natriuretic Factor - biosynthesis; Atrial Natriuretic Factor - genetics; Cardiomegaly - etiology; Cardiomegaly - metabolism; Cells, Cultured; Constriction, Pathologic; Culture Media, Conditioned - pharmacology; Fibroblasts - metabolism; Heart Ventricles; Male; Myocardium - cytology; Myocardium - metabolism; Norepinephrine - pharmacology; Prazosin - pharmacology; Propranolol - pharmacology; Rats; Rats, Sprague-Dawley; RNA, Messenger - biosynthesis; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Up-Regulation - drug effects
• ISSN: 0021-9738
• DOI: 10.1172/jci117485

Transforming growth factor-beta 1 (TGF-beta 1) is a peptide growth factor that may play a role in the myocardial response to hypertrophic stimuli. However, the cellular distribution, mechanism of induction, and source of increased TGF-beta 1 in response to hypertrophic stimuli are not known. We tested the hypothesis that the cardiac myocyte responds to hypertrophic stimuli with the increased expression of TGF-beta 1. In adult rat ventricular myocardium freshly dissociated into myocyte and nonmyocyte cellular fractions, the preponderance of TGF-beta 1 mRNA visualized by Northern hybridization was in the nonmyocyte fraction. Abdominal aortic constriction (7 d) and subcutaneous norepinephrine infusion (36 h) each caused ventricular hypertrophy associated with 3.1-fold and 3.8-fold increases, respectively, in TGF-beta 1 mRNA in the myocyte fraction, but had no effect on the level of TGF-beta 1 mRNA in the nonmyocyte fraction. In ventricular myocytes, norepinephrine likewise caused a 4.1-fold increase in TGF-beta 1 mRNA associated with an increase in TGF-beta bioactivity. This induction of TGF-beta 1 mRNA occurred at norepinephrine concentrations as low as 1 nM and was blocked by prazosin, but not propranolol. NE did not increase the TGF-beta 1 mRNA level in nonmyocytes, primarily fibroblasts, cultured from neonatal rat ventricle. Thus, the cardiac myocyte responds to two hypertrophic stimuli, pressure overload and norepinephrine, with the induction of TGF-beta 1. These data support the view that TGF-beta 1, released by myocytes and acting in an autocrine and/or paracrine manner, is involved in myocardial remodeling by hypertrophic stimuli.