Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta(1).
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 consequence of altered beta-adrenergic signaling, hearts from TGF-beta showed enhanced contractile responsiveness to isoproterenol stimulation. In conclusion, we conclude that TGF-beta(1) induces cardiac hypertrophy and enhanced beta-adrenergic signaling in vivo. The morphological alterations are either induced by direct effects of TGF-beta(1) or may at least in part result from increased beta-adrenergic signaling, which may contribute to excessive catecholamine stimulation during the transition from compensated hypertrophy to heart failure.
Klinik III für Innere Medizin, Universität zu Köln, 50924 Köln, Germany. Stephan.Rosenkranz@medizin.uni-koeln.de
Stephan
S
Rosenkranz
Markus
M
Flesch
Kerstin
K
Amann
Claudia
C
Haeuseler
Heiko
H
Kilter
Ute
U
Seeland
Klaus-Dieter
KD
Schlüter
Michael
M
Böhm
D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D011943:Receptors, Adrenergic, beta; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019204:GTP-Binding Proteins