Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase

Belge, Catharina [UCL] Hammond, Joanna [UCL] Dubois, Emilie [UCL] Manoury, Boris [UCL] Hamelet, Julien [UCL] Beauloye, Christophe [UCL] Markl, Andreas Pouleur, Anne-Catherine [UCL] Bertrand, Luc [UCL] Esfahani, Hrag [UCL] Jnaoui, Karima Götz, Konrad R Nikolaev, Viacheslav O Vanderper, Annelies Herijgers, Paul Lobysheva, Irina [UCL] Iaccarino, Guido Hilfiker-Kleiner, Denise Tavernier, Geneviève Langin, Dominique Dessy, Chantal [UCL] Balligand, Jean-Luc [UCL] et al.[show all]

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.