The role of Natriuretic Peptide Receptor C in atrial electrophysiological remodelling in hypertensive heart disease

Abstract

Atrial fibrillation (AF) is prevalent in hypertension in association with alterations in angiotensin II (Ang II) signaling. Natriuretic peptides (NPs) are a family of hormones with potent effects on atrial electrophysiology mediated in part through the NPR-C receptor. The goal of this study was to determine the role of NPR-C in atrial electrophysiological remodelling in Ang II treated mice (3 mg/kg/day for 3 weeks). Ang II treatment increased the susceptibility to AF in WT (P = 0.001) and was more severe in NPR-C-/- (P = 0.03) mice vs. saline controls. Action potential (AP) upstroke velocity (Vmax; P = 0.01) and peak Na+ current (INa; P < 0.001) were reduced in left atrial (LA) myocytes from Ang II treated WT mice, which was attributed to enhanced PKC⍺ signalling. Ang II differentially prolonged the AP in right atrial (RA; APD50; P < 0.001) and LA (P < 0.001) myocytes. In addition, Ang II reduced Ito in RA myocytes (P < 0.001) and to a greater extent in LA myocytes (P = 0.045). In the RA of NPR-C-/‑ mice, Ang II prolonged (P < 0.05) APD50 to a similar extent vs. WT. In contrast, Vmax was reduced and APD50 was prolonged by Ang II to a greater extent (P < 0.05) in the LA of NPR-C-/- vs. WT mice. Ito was similarly reduced (P<0.05) in the RA and LA of Ang II treated WT and NPR-C-/- mice. Co-treatment with cANF (NPR-C agonist) reduced the susceptibility to AF (P = 0.04) in WT mice vs. Ang II alone. Strikingly, APD50 was reduced (P = 0.01) and Ito was increased (P = 0.001) in the RA, but not LA, by cANF co-treatment. Collectively, these data demonstrate that NPR-C plays a critical role in modulating disease progression in the atria elicited by Ang II treatment.