Universität zu Köln

Huntgeburth, Michael, Tiemann, Klaus, Shahverdyan, Robert, Schlueter, Klaus-Dieter, Schreckenberg, Rolf, Gross, Marie-Luise, Moedersheim, Sonja, Caglayan, Evren, Mueller-Ehmsen, Jochen, Ghanem, Alexander, Vantler, Marius, Zimmermann, Wolfram H., Boehm, Michael and Rosenkranz, Stephan (2011). Transforming Growth Factor beta(1) Oppositely Regulates the Hypertrophic and Contractile Response to beta-Adrenergic Stimulation in the Heart. PLoS One, 6 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Background: Neuroendocrine activation and local mediators such as transforming growth factor-beta(1) (TGF-beta(1)) contribute to the pathobiology of cardiac hypertrophy and failure, but the underlying mechanisms are incompletely understood. We aimed to characterize the functional network involving TGF-beta(1), the renin-angiotensin system, and the beta-adrenergic system in the heart. Methods: Transgenic mice overexpressing TGF-beta(1) (TGF-beta(1)-Tg) were treated with a beta-blocker, an AT(1)-receptor antagonist, or a TGF-beta-antagonist (sTGF beta R-Fc), were morphologically characterized. Contractile function was assessed by dobutamine stress echocardiography in vivo and isolated myocytes in vitro. Functional alterations were related to regulators of cardiac energy metabolism. Results: Compared to wild-type controls, TGF-beta(1)-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-beta(1) overexpression increased the hypertrophic responsiveness to beta-adrenergic stimulation. In contrast, the inotropic response to beta-adrenergic stimulation was diminished in TGF-beta(1)-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-beta R-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic beta-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to beta-adrenergic stimulation without affecting TGF-beta(1) levels, whereas AT(1)-receptor blockade had no effect. The impaired contractile reserve in TGF-beta(1)-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by beta-adrenoceptor blockade. UCP-inhibition restored the contractile response to beta-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-beta(1) and UCP expression were elevated in heart failure in humans, and UCP - but not TGF-beta(1) - was downregulated by beta-blocker treatment. Conclusions: Our data support the concept that TGF-beta(1) acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the beta-adrenergic system in TGF-beta(1)-induced cardiac phenotype. Our data indicate for the first time, that TGF-beta(1) directly influences mitochondrial energy metabolism by regulating UCP3 expression. beta-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Huntgeburth, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Tiemann, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Shahverdyan, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlueter, Klaus-Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Schreckenberg, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Gross, Marie-Luise UNSPECIFIED UNSPECIFIED UNSPECIFIED Moedersheim, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Caglayan, Evren UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller-Ehmsen, Jochen UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghanem, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Vantler, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Wolfram H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehm, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenkranz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-485301
DOI:	10.1371/journal.pone.0026628
Journal or Publication Title:	PLoS One
Volume:	6
Number:	11
Date:	2011
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYOCARDIAL ENERGY-METABOLISM; TGF-BETA; UNCOUPLING PROTEINS; GENE-EXPRESSION; TRANSGENIC MICE; CARDIAC-HYPERTROPHY; UP-REGULATION; FIBROSIS; FAILURE; CARDIOMYOCYTES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48530