Alterations of beta -adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta 1

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 283; no. 3; pp. H1253 - H1262
• Main Authors: Rosenkranz, Stephan, Flesch, Markus, Amann, Kerstin, Haeuseler, Claudia, Kilter, Heiko, Seeland, Ute, Schluter, Klaus-Dieter, Bohm, Michael
• Format: Journal Article
• Language: English
• Published: 01.09.2002
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00578.2001

1  Klinik III für Innere Medizin, Universität zu Köln, 50924 Köln; 2  Pathologisches Institut, Universität Erlangen, Erlangen 91054; 3  Medizinische Klinik III, Universität des Saarlandes, Homburg-Saar 66421; and 4  Physiologisches Institut, Justus-Liebig-Universität Giessen, Giessen 35390, Germany Transforming growth factor- 1 (TGF- 1 ) promotes or inhibits cell proliferation and induces fibrotic processes and extracellular matrix production in numerous cell types. Several cardiac diseases are associated with an increased expression of TGF- 1 mRNA, particularly during the transition from stable cardiac hypertrophy to heart failure. In vitro studies suggest a link between TGF- 1 signaling and the -adrenergic system. However, the in vivo effects of this growth factor on myocardial tissue have been poorly identified. In transgenic mice overexpressing TGF- 1 (TGF- ), we investigated the in vivo effects on cardiac morphology, -adrenergic signaling, and contractile function. When compared with nontransgenic controls (NTG), TGF- mice revealed significant cardiac hypertrophy (heart weight, 164 ± 7 vs. 130 ± 3 mg, P < 0.01; heart weight-to-body weight ratio, 6.8 ± 0.3 vs. 5.1 ± 0.1 mg/g, P  < 0.01), accompanied by interstitial fibrosis. These morphological changes correlated with an increased expression of hypertrophy-associated proteins such as atrial natriuretic factor (ANF). Furthermore, overexpression of TGF- 1 led to alterations of -adrenergic signaling as myocardial -adrenoceptor density increased from 7.3 ± 0.3 to 11.2 ± 1.1   fmol/mg protein ( P < 0.05), whereas the expression of -adrenoceptor kinase-1 and inhibitory G proteins decreased by 56 ± 9.7% and 58 ± 7.6%, respectively ( P < 0.05). As a consequence of altered -adrenergic signaling, hearts from TGF- showed enhanced contractile responsiveness to isoproterenol stimulation. In conclusion, we conclude that TGF- 1 induces cardiac hypertrophy and enhanced -adrenergic signaling in vivo. The morphological alterations are either induced by direct effects of TGF- 1 or may at least in part result from increased -adrenergic signaling, which may contribute to excessive catecholamine stimulation during the transition from compensated hypertrophy to heart failure. cardiac hypertrophy; heart failure; G proteins