Eric Chong1, Shih-Lin Chang1, Ya-Wen Hsiao2, Rahul Singhal1, Shuen-Hsin Liu1, Trung Leha1, Wen-Yu Lin1, Chiao-Po Hsu3, Yao-Chang Chen4, Yi-Jen Chen5, Tsu-Juey Wu6, Satoshi Higa7, Shih-Ann Chen8. 1. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan. 2. Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan. 3. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. 4. Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan. 5. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan. 6. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taichung Veterans General Hospital, Taichung, Taiwan. 7. Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan. 8. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: epsachen@ms41.hinet.net.
Abstract
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.
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:Resveratroldecreases left atrial fibrosis and regulates variation in ion channels to reduce AF through the PI3K/AKT/eNOS signaling pathway.