Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling |
| |
| Institution: | 1. Department of Vascular and Endovascular Surgery, Henan Provincial People''s Hospital, Zhengzhou 450003, China;2. Department of Anaesthesia, Fuwai Central China Cardiovascular Hospital, Zhengzhou 450000, China;3. Department of Vascular and Endovascular Surgery, The Affiliated People''s Hospital, Zhengzhou University, Zhengzhou 450003, China;4. Department of Vascular and Endovascular Surgery, The Affiliated People''s Hospital, Henan University, Zhengzhou 450003, China;5. Department of Anaesthesia, The Affiliated People’s Hospital, Zhengzhou University, Zhengzhou 450003, China;6. Department of Anaesthesia, The Affiliated People’s Hospital, Henan University, Zhengzhou 450003, China;1. College of Medicine and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates;2. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;3. Center for Translational Medicine, School of Medicine, Temple University, Philadelphia, PA, USA;4. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada;1. Department of Physiology and Pathophysiology, Xi''an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases (Xi''an Jiaotong University), Ministry of Education, Xi''an 710061, China;2. Department of Anesthesiology, First Affiliated Hospital of Xi''an Jiaotong University, Xi''an 710061, China;1. Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China;2. Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA;3. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA |
| |
| 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. |
| |
| Keywords: | Arrhythmias Glycogen synthase kinase-3 Heme oxygenase-1 Nuclear factor erythroid-2-related factor 2 Lithium Free radicals |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
