NPR-C (Natriuretic Peptide Receptor-C) Modulates the Progression of Angiotensin II-Mediated Atrial Fibrillation and Atrial Remodeling in Mice

Circ Arrhythm Electrophysiol. 2019 Jan;12(1):e006863. doi: 10.1161/CIRCEP.118.006863.


Background: Atrial fibrillation (AF) commonly occurs in hypertension and in association with elevated Ang II (angiotensin II) levels. The specific mechanisms underlying Ang II-mediated AF are unclear, and interventions to prevent the effects of Ang II are lacking. NPs (natriuretic peptides), which elicit their effects through specific NP receptors, including NPR-C (natriuretic peptide receptor-C), are cardioprotective hormones that affect cardiac structure and function.

Methods: This study used wild-type and NPR-C knockout (NPR-C-/-) mice to investigate the effects of Ang II (3 mg/kg per day for 3 weeks) on AF susceptibility and atrial function using in vivo electrophysiology, high-resolution optical mapping, patch clamping, and molecular biology. In some experiments, wild-type mice were cotreated with Ang II and the NPR-C agonist cANF (0.07-0.14 mg/kg per day) for 3 weeks.

Results: In wild-type mice, Ang II increased susceptibility to AF in association with a prolongation of P-wave duration, increased atrial refractory period, and slowed atrial conduction. These effects were exacerbated in Ang II-treated NPR-C-/- mice. Ang II prolonged action potential duration and reduced action potential upstroke velocity (Vmax). These effects were greater in left atrial myocytes from Ang II-treated NPR-C-/- mice. Ang II also increased fibrosis in both atria in wild-type mice, whereas Ang II-treated NPR-C-/- mice exhibited substantially higher fibrosis throughout the atria. Fibrotic responses were associated with changes in expression of profibrotic genes, including TGFβ and TIMP1. Cotreating wild-type mice with Ang II and the NPR-C agonist cANF dose dependently reduced AF inducibility by preventing some of the Ang II-induced changes in atrial myocyte electrophysiology and preventing fibrosis throughout the atria.

Conclusions: NPR-C may represent a new target for the prevention of Ang II-induced AF via protective effects on atrial electrical and structural remodeling.

Keywords: action potentials; extracellular matrix; fibrosis; ion channels; natriuretic peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Angiotensin II*
  • Animals
  • Atrial Fibrillation / chemically induced
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / metabolism*
  • Atrial Fibrillation / physiopathology
  • Atrial Remodeling*
  • Disease Models, Animal
  • Disease Progression
  • Fibrosis
  • Heart Atria / metabolism*
  • Heart Atria / physiopathology
  • Heart Rate
  • Hypertension / chemically induced
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Receptors, Atrial Natriuretic Factor / deficiency
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / metabolism*
  • Time Factors


  • Angiotensin II
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor C