Transforming Growth Factor beta(1) Oppositely Regulates the Hypertrophic and Contractile Response to beta-Adrenergic Stimulation in the Heart

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.