Enhanced Expression of ß3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling through Nitric Oxide Synthase
Background—ß1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. ß3-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 ß3-AR (ß3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). ß3-TG and WT had similar morphometric and haemodynamic parameters at baseline. ß3-AR co-localized with caveolin-3, eNOS and nNOS 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 ß3-TG mice, which also had less re-expression of fetal genes and TGF-beta1. Protection from Iso-induced hypertrophy was reversed by non-specific nitric oxide synthase (NOS) inhibition at low dose Iso, and by preferential nNOS inhibition at high dose Iso. Adenoviral overexpression of ß3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine (PE). Hypertrophy was restored upon NOS or Protein Kinase G inhibition. Mechanistically, ß3-AR overexpression inhibited PE-induced Nuclear Factor of Activated T-cells (NFAT) activation.
Conclusions—Cardiac-specific overexpression of ß3-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 ß3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.
- Received July 10, 2013.
- Revision received October 16, 2013.
- Accepted October 19, 2013.