Format

Send to

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

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

Author information

1
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (H.J.J., M. Mackasey, Y.L., J.K., A.W.K., R.A.R.), Cumming School of Medicine, University of Calgary, Alberta.
2
Department of Physiology and Pharmacology (H.J.J., M. Mackasey, Y.L., J.K., A.W.K., R.A.R.), Cumming School of Medicine, University of Calgary, Alberta.
3
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia (M. Moghtadaei, E.E.E., S.A.R.).
4
Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (J.M.T.).

Abstract

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

PMID:
30636477
DOI:
10.1161/CIRCEP.118.006863
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center