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: Michael Huntgeburth, Klaus Tiemann, Robert Shahverdyan, Klaus-Dieter Schlüter, Rolf Schreckenberg, Marie-Luise Gross, Sonja Mödersheim, Evren Caglayan, Jochen Müller-Ehmsen, Alexander Ghanem, Marius Vantler, Wolfram H Zimmermann, Michael Böhm, Stephan Rosenkranz
• Journal: PloS one (PLoS One) Vol. 6 Issue 11 Pg. e26628 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22125598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-1 Receptor Antagonists
• Adrenergic beta-Agonists
• Adrenergic beta-Antagonists
• Angiotensin II Type 1 Receptor Blockers
• Benzimidazoles
• Benzoates
• Ion Channels
• Mitochondrial Proteins
• Transforming Growth Factor beta1
• UCP3 protein, human
• Ucp3 protein, mouse
• Uncoupling Protein 3
• Metoprolol
• Isoproterenol
• Telmisartan

Topics

• Adrenergic beta-1 Receptor Antagonists (pharmacology)
• Adrenergic beta-Agonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Benzoates (pharmacology)
• Cardiomegaly (diagnostic imaging, genetics, metabolism)
• Cells, Cultured
• Echocardiography, Stress
• Gene Expression Regulation (drug effects)
• Heart (drug effects, physiology)
• Humans
• Ion Channels (genetics)
• Isoproterenol (pharmacology)
• Metoprolol (pharmacology)
• Mice
• Mice, Transgenic
• Mitochondrial Proteins (genetics)
• Myocardial Contraction (drug effects)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Telmisartan
• Transforming Growth Factor beta1 (genetics, metabolism)
• Uncoupling Protein 3