Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

Background: Neuroendocrine activation and local mediators such as transforming growth factor-b1 (TGF-b1) 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-b1, the renin-angiotensin system, and the b-adrenergic system in the heart. Methods: Transgenic mice overexpressing TGF-b1 (TGF-b1-Tg) were treated with a b-blocker, an AT1-receptor antagonist, or a TGF-b-antagonist (sTGFbR-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-b1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-b1 overexpression increased the hypertrophic responsiveness to b-adrenergic stimulation. In contrast, the inotropic response to b-adrenergic stimulation was diminished in TGF-b1-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-bR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic b-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to b-adrenergic stimulation without affecting TGF-b1 levels, whereas AT1-receptor blockade had no effect. The impaired contractile reserve in TGF-b1-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by b-adrenoceptor blockade. UCP-inhibition restored the contractile response to b-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-b1 and UCP expression were elevated in heart failure in humans, and UCP – but not TGF-b1 – was downregulated by b-blocker treatment. Conclusions: Our data support the concept that TGF-b1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the b-adrenergic system in TGF-b1-induced cardiac phenotype. Our data indicate for the first time, that TGF-b1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. bblockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.