Key result
Chronic beta-blocker treatment with metoprolol or TGF-b antagonism prevented cardiac hypertrophy and restored the diminished inotropic response to beta-adrenergic stimulation in TGF-b1 transgenic mice.
Absolute Event Rate: 52% vs 16%
p-value: p=<0.05
TGF-β1 directly influences mitochondrial energy metabolism by regulating UCP3 expression, and β-blockers can normalize these mechanisms to prevent cellular hypertrophy and restore contractile reserve.
May support beta-blocker investigation in TGF-β1 models; leaves open translation to human contractile reserve.
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.
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Huntgeburth et al. (2011) studied Cardiac hypertrophy and heart failure. Metoprolol, telmisartan, or soluble TGF-b receptor-Fc (sR-Fc) vs. Untreated TGF-b1 transgenic mice and wild-type controls was evaluated on Relative increase in LVEF at peak dobutamine stress (p=<0.05). Chronic beta-blocker treatment with metoprolol or TGF-b antagonism prevented cardiac hypertrophy and restored the diminished inotropic response to beta-adrenergic stimulation in TGF-b1 transgenic mice.
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