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

Li, Xin; Rao, Fang; Deng, Chun‐Yu; Wei, Wei; Liu, Fang‐Zhou; Yang, Hui; Wang, Zhao‐Yu; Kuang, Su‐Juan; Chen, Xiao‐Yan; Xue, Yu‐Mei; Wu, Shu‐Lin

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 ERK1/2 kinase activation. Our findings represent a potential pathogenic mechanism in AF.

MACROPHAGES; MUSCLE cells; CYTOKINE genetics; MICRORNA genetics; SINUS arrhythmia; PHYSIOLOGY

Clinical & Experimental Pharmacology & Physiology, 2017, Vol 44, Issue 7, p771

0305-1870

Academic Journal

10.1111/1440-1681.12766