Quercetin down-regulates MCP-1 expression in autoimmune myocarditis via ERK1/2-C/EBPβ pathway: An integrative approach using network pharmacology and experimental models

Myocarditis is one of the common causes of sudden death in adolescents, and autoimmune response and inflammation play an essential role in the development of myocarditis. Quercetin is a natural flavonoid compound with anti-inflammatory and cardioprotective effects. However, the mechanism of quercetin in autoimmune myocarditis remains unclear. This study observed that quercetin significantly improved cardiac function, inflammation and fibrosis in mice with experimental autoimmune myocarditis (EAM). In addition, Network pharmacology predicts the key target C/EBPβ and signalling pathway MAPK for quercetin treatment of autoimmune myocarditis. CESTA and DARTS experiments verified that quercetin and C/EBPβ have strong binding ability. It is shown that quercetin down-regulates MCP-1 expression in H9C2 cells by dephosphorylation of ERK1/2 and C/EBPβ. Specifically, quercetin reduced the binding of C/EBPβ to the MCP-1 promoter, resulting in decreased expression of MCP-1, which was associated with decreased ERK1/2 dependent phosphorylation at the C/EBPβ threonine 188 site. This inhibitory effect of quercetin could be further enhanced by the ERK1/2 inhibitor PD98059. The biological relevance of this regulatory network is demonstrated in EAM mice. In conclusion, these results illustrate the protective effect of quercetin against autoimmune myocarditis. A novel regulatory mechanism was revealed, namely the down-regulation of MCP-1 through the ERK1/2-C/EBPβ axis. This provides a new therapeutic strategy for autoimmune myocarditis.

Autoimmune myocarditis; C/EBPβ; ERK1/2; MCP-1; Quercetin.