Melittin ameliorates CVB3-induced myocarditis via activation of the HDAC2-mediated GSK-3β/Nrf2/ARE signaling pathway

Biochem Biophys Res Commun. 2016 Nov 4;480(1):126-131. doi: 10.1016/j.bbrc.2016.09.135. Epub 2016 Sep 28.


Viral myocarditis (VMC) is characterized as an inflammatory process of the myocardium and can be fatal in infants and children. Melittin is a major polypeptide in honey bee venom that has been traditionally used against inflammation. However, its effect on VMC and the underlying molecular mechanism has not been reported. In this study, BALB/c mice were intraperitoneally injected with CVB3 to build a VMC model and treated with melittin. The results showed that melittin increased the mice's body weight and inhibited CVB3 replication. HE staining also showed that melittin alleviated myocardial injury in the VMC model. Flow cytometry showed that melittin inhibited myocardial cell apoptosis; in addition, real-time PCR showed that melittin decreased the expression of bax and caspase-3, and increased the expression of bcl-2. The results of echocardiographic examination showed that melittin improved cardiac function. Moreover, melittin decreased the activity of AST, CK, HBDH and LDH, and decreased the production of IL-1β, IL-6, TNF-α and MCP-1 in CVB3-induced myocardial tissues. Finally, we also found that melittin increased the expression of HDAC2 and activated the GSK-3β/Nrf2/ARE signaling pathway, whereas these changes were reversed by inhibition of HDAC2 in VMC model mice. In conclusion, our results suggested that melittin ameliorates CVB3-induced myocarditis via activation of the HDAC2-mediated GSK-3β/Nrf2/ARE signaling pathway.

Keywords: CVB3; GSK-3β/Nrf2/ARE signaling pathway; HDAC2; Melittin; Myocarditis.

MeSH terms

  • Animals
  • Antioxidant Response Elements / drug effects
  • Coxsackievirus Infections / drug therapy*
  • Coxsackievirus Infections / metabolism
  • Cytokines / metabolism
  • Enterovirus B, Human / pathogenicity
  • Enzyme Activation / drug effects
  • Enzymes / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Heart / drug effects
  • Heart / virology
  • Histone Deacetylase 2 / metabolism*
  • Male
  • Melitten / pharmacology*
  • Mice, Inbred BALB C
  • Myocarditis / drug therapy*
  • Myocarditis / metabolism
  • Myocarditis / pathology
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Myocardium / pathology
  • NF-E2-Related Factor 2 / metabolism
  • Signal Transduction / drug effects


  • Cytokines
  • Enzymes
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Melitten
  • Glycogen Synthase Kinase 3 beta
  • Hdac2 protein, mouse
  • Histone Deacetylase 2