Transforming growth factor β 1 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-β 1 (TGF-β 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-β 1, the renin-angiotensin system, and the β-adrenergic system in the heart. Methods: Transgenic mice overexpressing TGF-β 1 (TGF-β 1-Tg) were treated with a β-blocker, an AT 1-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-β 1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β 1 overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β 1-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-β 1 levels, whereas AT 1-receptor blockade had no effect. The impaired contractile reserve in TGF-β 1-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-β 1 and UCP expression were elevated in heart failure in humans, and UCP - but not TGF-β 1 - was downregulated by β-blocker treatment. Conclusions: Our data support the concept that TGF-β 1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β 1-induced cardiac phenotype. Our data indicate for the first time, that TGF-β 1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism. © 2011 Huntgeburth et al.