Acetylcholine inhibits hypoxia-induced tumor necrosis factor-α production via regulation of MAPKs phosphorylation in cardiomyocytes.

Abstract

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.

• Authors: Dong-Ling Li, Jin-Jun Liu, Bing-Hang Liu, Hao Hu, Lei Sun, Yi Miao, Hai-Fei Xu, Xiao-Jiang Yu, Xin Ma, Jun Ren, Wei-Jin Zang
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 226 Issue 4 Pg. 1052-9 (Apr 2011) ISSN: 1097-4652 [Electronic] United States
• PMID: 20857413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• RNA, Messenger
• Reactive Oxygen Species
• Receptor, Muscarinic M2
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinases
• Caspase 3
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Animals
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Cell Hypoxia (drug effects)
• Enzyme Activation (drug effects)
• Gene Expression Regulation (drug effects)
• Mitogen-Activated Protein Kinases (metabolism)
• Myocytes, Cardiac (cytology, drug effects, enzymology)
• Phosphorylation (drug effects)
• RNA, Messenger (genetics, metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Receptor, Muscarinic M2 (metabolism)
• Time Factors
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)