Natriuretic Peptide Receptor-C Mitigates Angiotensin II Induced Fibrosis in the Atria and Sinoatrial Node

Abstract

Atrial fibrillation (AF) and sinoatrial node (SAN) dysfunction frequently occur in hypertension and in association with elevated angiotensin II (Ang II). Adverse fibrotic remodeling of the atria is a principle determinant of atrial arrhythmogenesis; however, the mechanisms underlying structural remodeling associated with Ang II-mediated atrial and SAN dysfunction remain unclear. Natriuretic peptides (NPs), which act through NP receptors, including NPR-C (natriuretic peptide receptor-C), are cardioprotective hormones that affect cardiac structure and function. Here, we investigated the role of NPR-C in Ang II-mediated structural remodeling of the atria and SAN. Wildtype (Wt) and NPR-C knockout (NPR-C-/-) mice were infused with Ang II (2.5mg/kg/day) or saline for 21 days. In some studies, mice were co-treated with Ang II and the NPR-C agonist cANF (0.07 or 0.14mg/kg/day). Atrial and SAN structure and function were assessed by histology, molecular biology, optical mapping and in vivo electrophysiology. Wt mice infused with Ang II demonstrated increased AF susceptibility along with slowed atrial and SAN conduction. These effects were worsened in Ang II infused NPR-C-/-mice. Ang II increased SAN and atrial fibrosis in Wt mice, whereas Ang II infused NPR-C-/-mice exhibited substantially higher fibrosis. Enhanced fibrotic remodeling was associated with increased expression of profibrotic genes, including collagens, Transforming Growth Factor-β (TGFβ), Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP1), and Lysyl-Oxidase (LOX). Co-treating Wt mice with Ang II alongside cANF reduced fibrosis, improved conduction velocity, reduced AF susceptibility, and prevented alterations in profibrotic genes. These studies provide new insight into the basis for profibrotic signaling in the SAN and atria in Ang II induced hypertensive heart disease. Our findings indicate that NPR-C may represent a new target for the prevention of Ang II-induced atrial and SAN dysfunction through effects on structural remodeling.