title: Inhibition of glycogen synthase kinase-3β prevents sympathetic hyperinnervation in infarcted rats.
abstract: We have demonstrated that nerve growth factor (NGF) expression in the myocardium is selectively increased during chronic stage of myocardial infarction, resulting in sympathetic hyperinnervation. Glycogen synthase kinase-3 (GSK-3) signal has been shown to play key roles in the regulation of cytoskeletal assembly during axon regeneration. We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction through attenuated NGF expression and Tau expression. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to either LiCl or SB216763, chemically unrelated inhibitors of GSK-3β, a combination of LiCl and SB216763, or vehicle for four weeks. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with excessive sympathetic reinnervation after infarction. Immunohistochemical analysis for sympathetic nerve also confirmed the change of myocardial norepinephrine. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administering either LiCl, SB216763, or combination. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those treated with GSK-3 inhibitors. Addition of SB216763 did not have additional beneficial effects compared with those seen in rats treated with LiCl alone. Furthermore, lithium treatment increased Tau1 and decreased AT8 and AT180 levels. Chronic use of lithium after infarction, resulting in attenuated sympathetic reinnervation by GSK-3 inhibition, may modify the arrhythmogenic response to programmed electrical stimulation.
authors.affiliation: Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan 709, Taiwan Department of Medicine, China Medical University, Taichung 40447, Taiwan Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Neuropsychiatry Center, China Medical University Hospital, Taichung 40447, Taiwan Graduate Institute of Immunology, China Medical University, Taichung 40447, Taiwan Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin 651, Taiwan Department of Neurosurgery, China Medical University-An Nan Hospital, Tainan 40447, 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 11031, Taiwan Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan ncchang@tmu.edu.tw.
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D015153:Blotting, Western; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000294:innervation*; D007150:Immunohistochemistry; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology*; D009416:Nerve Regeneration / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Arrhythmias; Tau protein; glycogen synthase kinase-3; lithium; myocardial infarction