Absence of natriuretic peptide clearance receptor attenuates TGF-1-induced selective atrial fibrosis and atrial fibrillation

Aims TGF-1 plays an important role in atrial fibrosis and atrial fibrillation (AF); previous studies have shown that the atria are more susceptible to TGF-1 mediated fibrosis than the ventricles. Natriuretic peptides (NPs) play an important role in cardiac remodelling and fibrosis, but the role of natriuretic peptide clearance (NPR-C) receptor is largely unknown. We investigated the role of NPR-C in modulating TGF-1 signalling in the atria. Methods and results MHC-TGF-1 transgenic (TGF-1-Tx) mice, which develop isolated atrial fibrosis and AF, were cross-bred with NPR-C knock-out mice (NPR-C-KO). Transverse aortic constriction (TAC) was performed in wild type (Wt) and NPR-C knockout mice to study. Atrial fibrosis and AF inducibility in a pathophysiologic model. Electrophysiology, molecular, and histologic studies were performed in adult mice. siRNA was used to interrogate the interaction between TGF-1 and NP signalling pathways in isolated atrial and ventricular fibroblasts/myofibroblasts. NPR-C expression level was 175.8-fold higher in the atria compared with the ventricle in Wt mice (P=0.009). Cross-bred mice demonstrated markedly decreased pSmad2 and collagen expression, atrial fibrosis, and AF compared with TGF-1-Tx mice with intact NPR-C. There was a marked reduction in atrial fibrosis gene expression and AF inducibility in the NPR-C-KO-TAC mice compared with Wt-TAC. In isolated fibroblasts, knockdown of NPR-C resulted in a marked reduction of pSmad2 (56 +/- 4% and 24 +/- 14% reduction in atrial and ventricular fibroblasts, respectively) and collagen (76 +/- 15% and 35 +/- 23% reduction in atrial and ventricular fibroblasts/myofibroblasts, respectively) in response to TGF-1 stimulation. This effect was reversed by simultaneously knocking down NPR-A but not with simultaneous knock down of PKG-1. Conclusion The differential response to TGF-1 stimulated fibrosis between the atria and ventricle are in part mediated by the abundance of NPR-C receptors in the atria.