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

Abstract

Transforming growth factor-β 1(TGF-β 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-β 1 mRNA, particularly during the transition from stable cardiac hypertrophy to heart failure. In vitro studies suggest a link between TGF-β 1 signaling and the β-adrenergic system. However, the in vivo effects of this growth factor on myocardial tissue have been poorly identified. In transgenic mice overexpressing TGF-β 1(TGF-β), we investigated the in vivo effects on cardiac morphology, β-adrenergic signaling, and contractile function. When compared with nontransgenic controls (NTG), TGF-β 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-β 1 led to alterations of β-adrenergic signaling as myocardial β-adrenoceptor density increased from 7.3 ± 0.3 to 11.2 ± 1.1 fmol/mg protein ( P < 0.05), whereas the expression of β-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 β-adrenergic signaling, hearts from TGF-β showed enhanced contractile responsiveness to isoproterenol stimulation. In conclusion, we conclude that TGF-β 1 induces cardiac hypertrophy and enhanced β-adrenergic signaling in vivo. The morphological alterations are either induced by direct effects of TGF-β 1 or may at least in part result from increased β-adrenergic signaling, which may contribute to excessive catecholamine stimulation during the transition from compensated hypertrophy to heart failure.