Cardiac salvage by tweaking with beta-3-adrenergic receptors

Cardiovasc Res. 2016 Jul 15;111(2):128-33. doi: 10.1093/cvr/cvw056. Epub 2016 Mar 21.


Overstimulation of the orthosympathetic system leads to cardiovascular cell and tissue damage through prolonged activation of β-1-2 adrenergic receptors (BARs). The more recent identification of the third isotype of BAR (B3AR) in cardiac myocytes and endothelial cells with a distinctive coupling and effect on cardiac function and remodelling introduced a new facet to this paradigm. In particular, B3AR is up-regulated in cardiac disease and less prone to homologous desensitization, which may reinforce its influence on the diseased myocardium. Mice with transgenic cardiac-specific expression of the human B3AR are protected from cardiac hypertrophy and fibrosis in response to neurohormonal stimulation. B3AR has also been implicated in cardiac protection after ischaemia-reperfusion and the benefits of exercise on the heart. Many of these salvage mechanisms are mediated by B3AR coupling to nitric oxide synthase (eNOS and nNOS) and downstream cGMP/protein kinase G signalling. Notably, B3AR exerts antioxidant protective effects on these and other signalling elements, which may subserve its protective properties in the setting of chronic heart failure. Additional vasorelaxing properties and paracrine NO-mediated signalling by B3AR in endothelium, together with systemic metabolic effects on beige/brown fat complete the pleiotropic protective properties of this new therapeutic target.

Keywords: adrenergic receptor; catecholamines; heart failure; hypertrophy; nitric oxide; remodelling.

Publication types

  • Review

MeSH terms

  • Acetanilides / therapeutic use
  • Adrenergic beta-3 Receptor Agonists / therapeutic use
  • Animals
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Heart Diseases / drug therapy
  • Heart Diseases / metabolism*
  • Heart Diseases / pathology
  • Heart Diseases / physiopathology
  • Humans
  • Myocardial Contraction
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Receptors, Adrenergic, beta-3 / drug effects
  • Receptors, Adrenergic, beta-3 / metabolism*
  • Signal Transduction* / drug effects
  • Thiazoles / therapeutic use
  • Ventricular Remodeling


  • Acetanilides
  • Adrenergic beta-3 Receptor Agonists
  • Receptors, Adrenergic, beta-3
  • Thiazoles
  • Nitric Oxide
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type III
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP
  • mirabegron