Alterations of β-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-β1

作者：Stephan Rosenkranz, Markus Flesch, Kerstin Amann, Claudia Haeuseler, Heiko Kilter, Ute Seeland, Klaus‐Dieter Schlüter, Michael C Böhm · 发表于：American Journal of Physiology-Heart and Circulatory Physiology · 年份：2002 · DOI：10.1152/ajpheart.00578.2001 · 被引用次数：299 · 研究领域：Cardiac Fibrosis and Remodeling、Receptor Mechanisms and Signaling、Phosphodiesterase function and regulation

Transforming growth factor-beta(1) (TGF-beta(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-beta(1) mRNA, particularly during the transition from stable cardiac hypertrophy to heart failure. In vitro studies suggest a link between TGF-beta(1) signaling and the beta-adrenergic system. However, the in vivo effects of this growth factor on myocardial tissue have been poorly identified. In transgenic mice overexpressing TGF-beta(1) (TGF-beta), we investigated the in vivo effects on cardiac morphology, beta-adrenergic signaling, and contractile function. When compared with nontransgenic controls (NTG), TGF-beta 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-beta(1) led to alterations of beta-adrenergic signaling as myocardial beta-adrenoceptor density increased from 7.3 +/- 0.3 to 11.2 +/- 1.1 fmol/mg protein (P < 0.05), whereas the expression of beta-adrenoceptor kinase-1 and inhibitory G proteins decreased by 56 +/- 9.7% and 58 +/- 7.6%, respectively (P < 0.05). As a conseque...