RESUMEN
BACKGROUND: Neuroendocrine activation and local mediators such as transforming growth factor-ß1 (TGF-ß1) 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-ß1, the renin-angiotensin system, and the ß-adrenergic system in the heart. METHODS: Transgenic mice overexpressing TGF-ß1 (TGF-ß1-Tg) were treated with a ß-blocker, an AT1-receptor antagonist, or a TGF-ß-antagonist (sTGFßR-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-ß1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-ß1 overexpression increased the hypertrophic responsiveness to ß-adrenergic stimulation. In contrast, the inotropic response to ß-adrenergic stimulation was diminished in TGF-ß1-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-ßR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic ß-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to ß-adrenergic stimulation without affecting TGF-ß1 levels, whereas AT1-receptor blockade had no effect. The impaired contractile reserve in TGF-ß1-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by ß-adrenoceptor blockade. UCP-inhibition restored the contractile response to ß-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-ß1 and UCP expression were elevated in heart failure in humans, and UCP--but not TGF-ß1--was downregulated by ß-blocker treatment. CONCLUSIONS: Our data support the concept that TGF-ß1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the ß-adrenergic system in TGF-ß1-induced cardiac phenotype. Our data indicate for the first time, that TGF-ß1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. ß-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.