Involvement of Src in L-type Ca channel depression induced by macrophage migration inhibitory factor in atrial myocytes |
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Authors: | Fang Rao Chun-Yu Deng Shu-Lin Wu Ding-Zhang Xiao Xi-Yong Yu Su-Juan Kuang Qiu-Xiong Lin Zhi-Xin Shan |
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Affiliation: | aDepartment of Cardiology, Guangdong Cardiovascular Institute, 96 Dongchuan Road, Guangzhou 510080, PR China;bGuangdong General Hospital, Guangzhou 510080, PR China;cGuangdong Academy of Medical Sciences, Guangzhou 510080, PR China |
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Abstract: | Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that controls inflammatory processes, and inflammation is known to play an important role in the pathogenesis of atrial fibrillation (AF). The present study sought to investigate whether MIF expression is responsible for the changes in L-type Ca2+ currents (ICa,L) seen in AF. Whole-cell voltage-clamp recordings and biochemical assays were used to study the regulation and expression of ICa,L in human atrial myocytes and in HL-1 cells. Basal ICa,L was reduced in AF compared to sinus rhythm (SR) controls, mRNA and protein levels of the pore-forming α1C subunit of L-type Ca2+ channel (LCC α1C) were also decreased, while MIF expression levels were increased in AF. Levels of Src and activated Src (p-Src Y416) were higher in AF than in SR. Treatment of atrial myocytes from a patient with SR with human recombinant MIF (rMIF) (40 nM, 1 h) was found to depress ICa,L amplitudes, while mouse rMIF (20 or 40 nM, 24 h) suppressed peak ICa,L in HL-1 cells by 69% and 83% in a concentration-dependent manner. Mouse rMIF impaired the time-dependent recovery from inactivation of ICa,L and down-regulated LCC α1C subunit levels. The depression of ICa,L and decrease of LCC protein levels induced by rMIF were prevented by the Src inhibitors genistein and PP1. These results implicate MIF in the electrical remodeling that accompanies AF, probably by decreasing ICa,L amplitudes through impairment of channel function, down-regulation of LCC α1C subunit levels, and the activation of c-Src kinases in atrial myocytes. |
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Keywords: | Macrophage migration inhibitory factor HL-1 cells Ca2+ channel Atrial fibrillation Protein kinases |
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