Circulation 2014 Jan 4;129(4):451-62. Epub 2013 Nov 4.
Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH), Université Catholique de Louvain, Brussels, Belgium (C.B., J. Hammond, E.D.-D., B.M., J. Hamelet, A.M., H.E., K.J., I.L., C.D., J.-L.B.); Pole of Cardiovascular Pathology and Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium (C.B., A.-C.P., L.B.); the Division of Cardiology and Pneumology, University of Goettingen, Goettingen, Germany (K.R.G., V.O.N.); the Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Belgium (A.V., P.H.); the Department of Medicine and Surgery, University of Salerno and RCCS "Multimedica," Milano, Italy (G.I.); Molecular Cardiology, Medizinische Hochschule Hannover, Germany (D.H.-K.); and Université Paul Sabatier, Inserm UMR 1048 - I2MC, Hôpitaux de Toulouse, France (G.T., D.L.).
Background: β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown.
Methods And Results: Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation.
Conclusions: Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.
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