Acetylcholine Inhibits Hypoxia-Induced Tumor Necrosis Factor-alpha Production via Regulation of MAPKs Phosphorylation in Cardiomyocytes

作者：Li, Dong-Ling; Liu, Jin-Jun; Liu, Bing-Hang; Hu, Hao; Sun, Lei; Miao, Yi; Xu, Hai-Fei; Yu, Xiao-Jiang; Ma, Xin; Ren, Jun; Zang, Wei-Jin^*

来源：Journal of Cellular Physiology, 2011, 226(4): 1052-1059.

DOI：10.1002/jcp.22424

• CHRONIC HEART-FAILURE
• TNF-ALPHA
• MYOCARDIAL-ISCHEMIA
• ISCHEMIA/REPERFUSION INJURY
• ANTIINFLAMMATORY PATHWAY
• SYSTEMIC INFLAMMATION
• VAGAL-STIMULATION
• RAT-HEART
• ACTIVATION
• EXPRESSION

Recent findings have reported that up-regulation of tumor necrosis factor-alpha (TNF-alpha) 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-alpha production in cardiomyocytes after hypoxia. The concentration of extracellular TNF-alpha was increased in a time-dependent manner during hypoxia. Furthermore, ACh treatment also inhibited hypoxia-induced TNF-alpha 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-alpha production. We have identified a novel pathway by which ACh mediates cardioprotection against hypoxic injury in cardiomyocytes. J. Cell. Physiol. 226: 1052-1059, 2011.

• 出版日期2011-4
• 单位西安交通大学