Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
J Cell Physiol. 2011 Apr;226(4):1052-9. doi: 10.1002/jcp.22424.
Recent findings have reported that up-regulation of tumor necrosis factor-alpha (TNF-α) induced by myocardial hypoxia aggravates cardiomyocyte injury. Acetylcholine (ACh), the principle vagal neurotransmitter, protects cardiomyocytes against hypoxia by inhibiting apoptosis. However, it is still unclear whether ACh regulates TNF-α production in cardiomyocytes after hypoxia. The concentration of extracellular TNF-α was increased in a time-dependent manner during hypoxia. Furthermore, ACh treatment also inhibited hypoxia-induced TNF-α mRNA and protein expression, caspase-3 activation, cell death and the production of reactive oxygen species (ROS) in cardiomyocytes. ACh treatment prevented the hypoxia-induced increase in p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, and increased extracellular signal-regulated kinase (ERK) phosphorylation. Co-treatment with atropine, a non-selective muscarinic acetylcholine receptor antagonist, or methoctramine, a selective type-2 muscarinic acetylcholine (M(2) ) receptor antagonist, abrogated the effects of ACh treatment in hypoxic cardiomyocytes. Co-treatment with hexamethonium, a non-selective nicotinic receptor antagonist, and methyllycaconitine, a selective alpha7-nicotinic acetylcholine receptor antagonist, had no effect on ACh-treated hypoxic cardiomyocytes. In conclusion, these results demonstrate that ACh activates the M(2) receptor, leading to regulation of MAPKs phosphorylation and, subsequently, down-regulation of TNF-α production. We have identified a novel pathway by which ACh mediates cardioprotection against hypoxic injury in cardiomyocytes.
最近的研究结果表明，心肌缺氧诱导的肿瘤坏死因子-α（TNF-α）上调加剧了心肌细胞损伤。乙酰胆碱（ACh）是主要的迷走神经递质，通过抑制细胞凋亡来保护心肌细胞免受缺氧的影响。然而，ACh 是否在缺氧后调节心肌细胞中 TNF-α 的产生仍不清楚。在缺氧过程中，细胞外 TNF-α的浓度呈时间依赖性增加。此外，ACh 处理还抑制了缺氧诱导的 TNF-α mRNA 和蛋白表达、半胱天冬酶-3 的激活、心肌细胞死亡和活性氧（ROS）的产生。ACh 处理可防止缺氧诱导的 p38 丝裂原活化蛋白激酶（MAPK）和 c-Jun N 端激酶（JNK）磷酸化增加，并增加细胞外信号调节激酶（ERK）磷酸化。用阿托品（一种非选择性毒蕈碱乙酰胆碱受体拮抗剂）或甲硫氧嘧啶（一种选择性 2 型毒蕈碱乙酰胆碱（M2）受体拮抗剂）共同处理可消除 ACh 在缺氧心肌细胞中的作用。用六烃季铵（一种非选择性烟碱受体拮抗剂）和甲基六氢烟碱（一种选择性α7 烟碱乙酰胆碱受体拮抗剂）共同处理对 ACh 处理的缺氧心肌细胞没有影响。总之，这些结果表明 ACh 激活 M2 受体，导致 MAPKs 磷酸化的调节，随后下调 TNF-α 的产生。我们已经确定了一种新的途径，ACh 通过该途径介导对缺氧心肌损伤的心肌保护作用。
