Sacubitril/valsartan Decreased Atrial Fibrillation Susceptibility by Inhibiting Angiotensin II-induced Atrial Fibrosis through p-Smad2/3, p-JNK, and p-p38 Signaling Pathways

Background: Sacubitril/valsartan (SAC/VAL), combined inhibitors of angiotensin receptor (AT-R) and neprilysin receptor, prevents Angiotensin Ⅱ (AngⅡ) from binding AT 1 -R and blocks degradation of natriuretic peptides. Despite its efficacy in reducing ventricular fibrosis and preserving cardiac functions, which has been extensively demonstrated in myocardial infarction or pressure overload models, few studies have been conducted to determine whether SAC/VAL could attenuate atrial fibrosis and decrease atrial fibrillation (AF) susceptibility. Methods: Sprague-Dawley rats were divided into three groups after implantation of an osmotic pump preloaded with AngⅡ and received corn oil, VAL, or SAC/VAL treatment for 28 days. Electrophysiological study was performed to determine inducibility and duration of AF. Echocardiography was performed before and 28 days after osmotic mini-pump implantation to evaluate cardiac functions. Enzyme-linked immunosorbent assay was perfomed to detect the serum concentration of atrial natriuretic peptide (ANP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and AngⅡ. Masson staining was performed to determine the extent of interstitial fibrosis. Immunohistochemical, and immunofluorescence staining as well as transwell and MTT assay were also performed. Western blot analysis was perfomed to figure out how SAC/VAL exerts its anti-fibrosis effects in atriums. Results: After 28 days of AngⅡ stimulation, rats in SAC/VAL group exhibited reduced reduced extent of atrial fibrosis, inhibited proliferation, migration, and differentiation of atrial fibroblasts and decreased susceptibility to atrial fibrillation. We further found that SAC/VAL exerted its effect on AngⅡ-induced atrial fibrosis by inhibiting the p-Smad2/3, p-JNK, and p-p38 MAPK signaling pathways in vivo. Conclusions: Our study provided experimental evidence for the inhibition of atrial fibrosis and reduced susceptibility to AF by SAC/VAL. These results emphasize the importance of SAC/VAL in the prevention of AngⅡ-induced atrial fibrosis and may help to enrich the options for atrial fibrillation pharmacotherapy.