title: Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase.
abstract: 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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Catharina
authors.initials: C
authors.lastname: Belge
authors.forename: Joanna
authors.initials: J
authors.lastname: Hammond
authors.forename: Emilie
authors.initials: E
authors.lastname: Dubois-Deruy
authors.forename: Boris
authors.initials: B
authors.lastname: Manoury
authors.forename: Julien
authors.initials: J
authors.lastname: Hamelet
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
authors.forename: Andreas
authors.initials: A
authors.lastname: Markl
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Pouleur
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.forename: Hrag
authors.initials: H
authors.lastname: Esfahani
authors.forename: Karima
authors.initials: K
authors.lastname: Jnaoui
authors.forename: Konrad R
authors.initials: KR
authors.lastname: Götz
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Annelies
authors.initials: A
authors.lastname: Vanderper
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Irina
authors.initials: I
authors.lastname: Lobysheva
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Geneviève
authors.initials: G
authors.lastname: Tavernier
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D018377:Neurotransmitter Agents / Q000009:adverse effects / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D022702:Receptors, Adrenergic, beta-3; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D007545:Isoproterenol
keywords: catecholamines; hypertrophy; nitric oxide; receptors, adrenergic, beta