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.
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.
Free Radic Biol Med. 2014 Dec;77:71-81. doi: 10.1016/j.freeradbiomed.2014.08.022. Epub 2014 Sep 16.
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.
糖原合成酶激酶-3 (GSK-3) 信号已被证明在核因子红细胞 2 相关因子 2 (Nrf2) 的调节中发挥作用，Nrf2 是抗氧化基因的主要调节剂，包括血红素加氧酶-1 (HO-1)。我们评估了 GSK-3 抑制剂锂是否通过减弱神经生长因子 (NGF) 表达来减轻心肌梗死后心脏交感神经再支配，心肌梗死后处于高活性氧 (ROS) 状态，以及 Nrf2/HO-1 信号是否参与了保护作用。在结扎左前降支 24 小时后，雄性 Wistar 大鼠接受了 4 周的治疗。在梗塞后期间，通过心肌超氧化物、硝基酪氨酸和二氢乙啶荧光染色测量，氧化-硝化应激增加。协同作用，与假手术大鼠相比，在给予 vehicle 的大鼠中，心肌去甲肾上腺素水平和交感神经免疫组织化学分析显示神经支配显著增加。在给予 vehicle 的大鼠中，程序刺激时心律失常评分明显高于假手术组。这与 vehicle 治疗大鼠中 NGF 蛋白和 mRNA 的显著上调平行，而在给予 LiCl 后，这种上调减少。LiCl 刺激 Nrf2 的核易位和 Nrf2 靶基因 HO-1 的转录激活。与单独使用 LiCl 相比，用 wortmannin 抑制磷酯酰肌醇 3-激酶可减少 Nrf2 核易位和 HO-1 表达的增加。此外，在 Nrf2 抑制剂三叶草素、HO-1 抑制剂 SnPP 和过氧亚硝酸盐生成剂 SIN-1 的存在下，锂减弱的 NGF 水平被逆转，表明 Nrf2/HO-1/ROS 的作用。总之，锂通过抗氧化激活 Nrf2/HO-1 轴来减轻 NGF 诱导的交感神经支配，从而保护心室免受心律失常。
