Acetylcholine inhibits hypoxia-induced tumor necrosis factor-α production via regulation of MAPKs phosphorylation in cardiomyocytes
Version of Record online: 25 JAN 2011
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 226, Issue 4, pages 1052–1059, April 2011
How to Cite
Li, D.-L., Liu, J.-J., Liu, B.-H., Hu, H., Sun, L., Miao, Y., Xu, H.-F., Yu, X.-J., Ma, X., Ren, J. and Zang, W.-J. (2011), Acetylcholine inhibits hypoxia-induced tumor necrosis factor-α production via regulation of MAPKs phosphorylation in cardiomyocytes. J. Cell. Physiol., 226: 1052–1059. doi: 10.1002/jcp.22424
- Issue online: 25 JAN 2011
- Version of Record online: 25 JAN 2011
- Accepted manuscript online: 20 SEP 2010 12:00AM EST
- Manuscript Accepted: 1 SEP 2010
- Manuscript Received: 6 JAN 2010
- National Natural Science Foundation of China. Grant Numbers: 30930105, 30873058, 30770785
- National Basic Research Program of China. Grant Number: 2007CB512005
- CMB Distinguished Professorships Award. Grant Number: F510000/G16916404
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 (M2) 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 M2 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. J. Cell. Physiol. 226: 1052–1059, 2011. © 2010 Wiley-Liss, Inc.