| First Author | Belge C | Year | 2014 |
| Journal | Circulation | Volume | 129 |
| Issue | 4 | Pages | 451-62 |
| PubMed ID | 24190960 | Mgi Jnum | J:219317 |
| Mgi Id | MGI:5620089 | Doi | 10.1161/CIRCULATIONAHA.113.004940 |
| Citation | Belge C, et al. (2014) Enhanced expression of beta3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation 129(4):451-62 |
| abstractText | BACKGROUND: beta1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. beta3-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 beta3-AR (beta3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). beta3-TG and WT had similar morphometric and hemodynamic parameters at baseline. beta3-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 beta3-TG mice, which also had less re-expression of fetal genes and transforming growth factor beta1. 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 beta3-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, beta3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. CONCLUSIONS: Cardiac-specific overexpression of beta3-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 beta3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling. |
