Absence of natriuretic peptide clearance receptor attenuates TGF-β1-induced selective atrial fibrosis and atrial fibrillation
Abstract
TGF-β1 plays an important role in atrial fibrosis and atrial fibrillation (AF); previous studies have shown that the atria are more susceptible to TGF-β1 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-β1 signalling in the atria. MHC-TGF-β1 transgenic (TGF-β1-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-β1 and NP signalling pathways in isolated atrial and ventricular fibroblasts/myofibroblasts. NPR-C expression level was 17 ± 5.8-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-β1-Tx mice with intact NPR...Continue Reading
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