[Tolvaptan attenuates atrial remodeling in rats undergoing chronic intermittent hypoxia via miRNA-21]

Objective: To investigate the effects and potential mechanisms of tolvaptan on chronic intermittent hypoxia (CIH)-induced atrial remodeling in rats. Methods: A total of 45 Sprague-Dawley rats were divided into 3 groups by the random number table: control group, CIH group (6 h/d for 30 days), CIH plus tolvaptan group (8 mg·kg(-1)·d(-1) per gavage for 30 days). Echocardiography examination was performed after 30 days. Thereafter, 5 rats were randomly chosen for histology evaluation, 5 for molecular biological examinations and another 5 rats underwent isolated heart electrophysiology study in each group. Protein and mRNA expression levels of miRNA-21, Spry1, PTEN, ERK/p-ERK, MMP-9, PI3K, AKT/p-AKT were detected. Results: Compared to the rats in control group, rats in the CIH group showed higher atrial interstitial collagen deposition (P<0.001), increased atrial fibrillation inducibility (P=0.022). The results of immunohistochemistry staining showed that the mean optical density (MOD) of ERK, p-ERK and MMP-9 were significantly increased (all P<0.05), the MOD of Spry1 and PTEN were significantly decreased (both P<0.05), above changes could be significantly reversed by cotreatment with tolvaptan. No significant differences were detected in PI3K and AKT among the three groups (P>0.05). In addition, compared with rats in control group, mRNA levels of miRNA-21, MMP-9, PI3K, AKT, and protein levels of ERK, p-ERK, MMP-9 were significantly increased in CIH group(all P<0.05), whereas protein levels of Spry1, PI3K, p-AKT were significantly decreased (all P<0.05). Above changes could be significantly attenuated. Conclusions: CIH induces significant atrial remodeling in this rat model, which can be attenuated by tolvaptan possibly through modulating miRNA-21/Spry1/ERK/MMP-9 and miRNA-21/PTEN/PI3K/AKT signaling pathways.