Protective role of the cholinergic anti-inflammatory pathway in a mouse model of viral myocarditis.
BACKGROUND
Activation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor), has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis.


RESULTS
In a coxsackievirus B3 murine myocarditis model (Balb/c), nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group.


CONCLUSIONS
These results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.
Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Zheng
Z
Cheng
Department of Pediatric, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Ge
G
Li-Sha
Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Zhao
Z
Jing-Lin
Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Zhang
Z
Wen-Wu
Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Chen
C
Xue-Si
Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Chen
C
Xing-Xing
Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Li
L
Yue-Chun
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D029822:Enterovirus B, Human; D005786:Gene Expression Regulation / Q000187:drug effects*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000517:prevention & control* / Q000821:virology*; D009538:Nicotine / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D009538:Nicotine; D000157:Aconitine