Beneficial effects of tolvaptan on atrial remodeling induced by chronic intermittent hypoxia in rats

Abstract

Introduction: Atrial remodeling in the form of fibrosis is considered as the substrate for the development of atrial fibrillation (AF). The aim of this study was to investigate the effects of tolvaptan on chronic intermittent hypoxia (CIH) induced atrial remodeling and the mechanisms underlying such changes. Methods: A total of 45 Sprague-Dawley rats were randomized into three groups: Control group, CIH group, CIH with tolvaptan treatment (CIH-T) group (n = 15). CIH rats were subjected to CIH 6 hour/d for 30 days, and CIH-T rats were administrated tolvaptan while they received CIH. After the echocardiography examination, rats were sacrificed in the 31 days. In each group, 5 rats were randomly selected for isolated heart electrophysiology testing, for other 10 rats, the tissues of atria were sampled for histological and molecular biological experiments, Masson's trichrome staining was used to evaluate the extent of atrial fibrosis, expression levels of microRNA-21 (miR-21), Sprouty-1 (Spry1), phosphatase, and tensin homolog (PTEN), extracellular regulated protein kinase (ERK), phospho-extracellular regulated protein kinase (p-ERK), matrix metalloprotein 9 (MMP-9), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), phospho-protein kinase B (p-AKT), nuclear factor-k-gene binding (NF-κB), phosphor-nuclear factor-k-gene binding (p-NF-κB) were measured. Results: Compared to the Control rats, CIH rats showed higher atrial interstitial collagen deposition and AF inducibility, mRNA levels of miR-21, MMP-9, PI3K, AKT, and protein levels of ERK, p-ERK, MMP-9, NF-κB, p-NF-κB were significantly increased, whereas mRNA levels of Spry1, ERK, and protein levels of Spry1, PTEN, PI3K, AKT, p-AKT were significantly decreased. Treatment with tolvaptan attenuated CIH-induced atrial fibrosis, reduced AF inducibility, expression levels of miR-21 and its downstream factors were also improved. Conclusions: CIH-induced significant atrial remodeling in our rat model, which was attenuated by tolvaptan. These changes may be explained due to alterations in miR-21/Spry1/ERK/MMP-9, miR-21/PTEN/PI3K/AKT, and NF-κB pathways by tolvaptan.