title: Transforming growth factor β₁ oppositely regulates the hypertrophic and contractile response to β-adrenergic stimulation in the heart.
abstract: BACKGROUND
  Neuroendocrine activation and local mediators such as transforming growth factor-β₁ (TGF-β₁) 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-β₁, the renin-angiotensin system, and the β-adrenergic system in the heart.
  
  
  METHODS
  Transgenic mice overexpressing TGF-β₁ (TGF-β₁-Tg) were treated with a β-blocker, an AT₁-receptor antagonist, or a TGF-β-antagonist (sTGFβR-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-β₁-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β₁ overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β₁-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-βR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic β-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to β-adrenergic stimulation without affecting TGF-β₁ levels, whereas AT₁-receptor blockade had no effect. The impaired contractile reserve in TGF-β₁-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by β-adrenoceptor blockade. UCP-inhibition restored the contractile response to β-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-β₁ and UCP expression were elevated in heart failure in humans, and UCP--but not TGF-β₁--was downregulated by β-blocker treatment.
  
  
  CONCLUSIONS
  Our data support the concept that TGF-β₁ acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β₁-induced cardiac phenotype. Our data indicate for the first time, that TGF-β₁ directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.
authors: Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, Germany.
authors: Michael
authors: M
authors: Huntgeburth
authors: Klaus
authors: K
authors: Tiemann
authors: Robert
authors: R
authors: Shahverdyan
authors: Klaus-Dieter
authors: KD
authors: Schlüter
authors: Rolf
authors: R
authors: Schreckenberg
authors: Marie-Luise
authors: ML
authors: Gross
authors: Sonja
authors: S
authors: Mödersheim
authors: Evren
authors: E
authors: Caglayan
authors: Jochen
authors: J
authors: Müller-Ehmsen
authors: Alexander
authors: A
authors: Ghanem
authors: Marius
authors: M
authors: Vantler
authors: Wolfram H
authors: WH
authors: Zimmermann
authors: Michael
authors: M
authors: Böhm
authors: Stephan
authors: S
authors: Rosenkranz
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D025401:Echocardiography, Stress; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D007545:Isoproterenol / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077333:Telmisartan; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D000071247:Uncoupling Protein 3
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D007473:Ion Channels; D024101:Mitochondrial Proteins; D053773:Transforming Growth Factor beta1; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D008790:Metoprolol; D007545:Isoproterenol; D000077333:Telmisartan