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