Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation

Background Resveratrol has shown benefits in reducing ventricular remodeling and arrhythmias. Objective This study aimed to assess the therapeutic efficacy of resveratrol in reducing atrial fibrillation (AF) in a heart failure (HF) model and to explore the underlying mechanisms. Methods HF rabbits were created 4 weeks after undergoing coronary ligation. Group 1 (n = 6) was divided into subgroups of (a) normal rabbits, (b) HF sham rabbits, and (c) HF rabbits treated for 1 week with intraperitoneal injections of resveratrol, (d) resveratrol plus wortmannin, or (e) resveratrol plus diphenyleneiodonium chloride (DPI). All rabbits underwent epicardial catheter stimulation. Collagen content, messenger RNA and protein expression in ion channels, and phosphoinositide 3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) signaling pathways were studied in left atrial appendage (LAA) preparations. To investigate acute drug effects on left atrial electrophysiology, groups 2 a through 2e (n = 6 per group) were subjected to Langendorff perfusion. Results Higher AF inducibility was found in the HF group and groups that were given PI3K and eNOS inhibitors than in the normal and resveratrol-treated groups (P <.001). Histologic analysis of the LAA revealed a decrease in fibrosis in resveratrol-treated groups compared with the HF group (8.95% ± 1.53% vs 26.62% ± 2.19%, P <.001). In real-time polymerase chain reaction analysis, ion channels including Kv1.4, Kv1.5, KvLQT1, Kir2.1, Nav1.5, Cav1.2, NCX, SERCA2a, and phospholamban were upregulated by resveratrol. PI3K, AKT, and eNOS messenger RNA and protein expression were upregulated by resveratrol but were inhibited by the coadministration of wortmannin and DPI. Conclusion Resveratrol decreases left atrial fibrosis and regulates variation in ion channels to reduce AF through the PI3K/AKT/eNOS signaling pathway.