Involvement of ERK1/2 in Cx43 depression induced by macrophage migration inhibitory factor in atrial myocytes

Summary Connexin 43 (Cx43) plays an important role in the pathogenesis of atrial fibrillation ( AF ). The present study sought to investigate the effect of macrophage migration inhibitory factor ( MIF ), a pleiotropic cytokine, on Cx43 expression and activity and determine the intracellular signalling pathways. Cx43 protein and mRNA levels were assayed using immunofluorescence, real‐time polymerase chain reaction ( PCR ), and western blot. We found that increased MIF and extracellular regulated protein kinases ( ERK ) expression was accompanied by a significant reduction in Cx43 protein expression in atrial tissues from patients with AF compared with those with sinus rhythm. In cultured atrium‐derived myocytes ( HL ‐1 cells), mouse recombinant‐ MIF ( rMIF , 20 or 40 nmol/L, 24 hours) down‐regulated gene and protein expression of Cx43 in a concentration‐dependent manner. U0126, a specific inhibitor of mitogen‐activated protein kinase kinase ( MAPKK ) could reverse the decrease in expression of Cx43 protein induced by rMIF . Further studies revealed that rMIF (40 nmol/L, 15, 30, and 45 minutes) was able to stimulate phospho‐Erk1/2 (Thr202/Tyr204) production in a time‐dependent manner. These results suggest that MIF is involved in the pathogenesis of AF , probably by down‐regulating the protein and gene expression of Cx43 via ERK 1/2 kinase activation. Our findings represent a potential pathogenic mechanism in AF.