Abstract
Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but not angiotensin II, stimulated MIF expression in HL-1 cells. H2O2-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H2O2-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.
Highlights
Recent evidence indicates that inflammation plays an important role in the pathology of atrial fibrillation (AF)
To determine whether migration inhibitory factor (MIF) was regulated by redox stress in atrial myocytes, HL-1 cells were incubated in medium containing 100 or 300 mM H2O2 for 6 h
We demonstrated that 1) MIF was expressed in the cytoplasm of HL-1 cells; 2) levels of MIF expression were increased significantly by H2O2, but not Ang II, in a dosedependent manner; 3) this MIF expression was completely inhibited by treatment with the tyrosine kinase inhibitors genistein and PP1, as well as the specific protein kinase C (PKC) inhibitor GF109203X
Summary
Recent evidence indicates that inflammation plays an important role in the pathology of atrial fibrillation (AF). Inflammation is associated with activation of a variety of cells including lymphocytes, monocytes/ macrophages, fibroblasts, and cardiac myocytes, which express and secrete proinflammatory cytokines such as interleukin 6, tumor necrosis factor a, and C-reactive protein. These cytokines can modulate atrial functions and atrial remodeling, leading to development of AF [1,2,3,4,5,6,7]. The regulation of MIF production in atrial myocytes remains unclear
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