title: Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling.
abstract: Glycogen synthase kinase-3 (GSK-3) signaling has been shown to play a role in the regulation of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of antioxidant genes, including heme oxygenase-1 (HO-1). We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction, a status of high reactive oxygen species (ROS), by attenuating nerve growth factor (NGF) expression and whether Nrf2/HO-1 signaling is involved in the protection. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats were treated for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress, as measured by myocardial superoxide, nitrotyrosine, and dihydroethidium fluorescent staining. In concert, myocardial norepinephrine levels and immunohistochemical analysis of sympathetic nerve revealed a significant increase in innervation in vehicle-treated rats compared with sham-operated rats. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those in sham. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administration of LiCl. LiCl stimulated the nuclear translocation of Nrf2 and the transactivation of the Nrf2 target gene HO-1. Inhibition of phosphoinositide 3-kinase by wortmannin reduced the increase in Nrf2 nucleus translocation and HO-1 expression compared with lithium alone. In addition, the lithium-attenuated NGF levels were reversed in the presence of the Nrf2 inhibitor trigonelline, HO-1 inhibitor SnPP, and peroxynitrite generator SIN-1, indicating the role of Nrf2/HO-1/ROS. In conclusion, lithium protects against ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via antioxidant activation of the Nrf2/HO-1 axis.
authors.affiliation: Cardiology Section, Department of Medicine, China Medical University-An Nan Hospital, Tainan 709, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Neuropsychiatry Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; Department of Neurosurgery, China Medical University-An Nan Hospital, Tainan 709, Taiwan; Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: ncchang@tmu.edu.tw.
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects / Q000294:innervation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D017208:Rats, Wistar; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects
chemical_list: D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C009560:trigonelline; D020932:Nerve Growth Factor; D051547:Heme Oxygenase-1; D018021:Lithium Chloride
keywords: Arrhythmias; Free radicals; Glycogen synthase kinase-3; Heme oxygenase-1; Lithium; Nuclear factor erythroid-2-related factor 2