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

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

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish
Pages (from-to)451-462
Number of pages12
JournalCirculation
Volume129
Issue number4
DOIs
Publication statusPublished - Jan 28 2014

Keywords

  • Catecholamines
  • Hypertrophy
  • Nitric oxide
  • Receptors, adrenergic, beta

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Belge, C., Hammond, J., Dubois-Deruy, E., Manoury, B., Hamelet, J., Beauloye, C., Markl, A., Pouleur, A. C., Bertrand, L., Esfahani, H., Jnaoui, K., Götz, K. R., Nikolaev, V. O., Vanderper, A., Herijgers, P., Lobysheva, I., Iaccarino, G., Hilfiker-Kleiner, D., Tavernier, G., ... Balligand, J. L. (2014). Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation, 129(4), 451-462. https://doi.org/10.1161/CIRCULATIONAHA.113.004940