Involvement of Src in L-type Ca2+ channel depression induced by macrophage migration inhibitory factor in atrial myocytes.
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 (I(Ca,L)) seen in AF. Whole-cell voltage-clamp recordings and biochemical assays were used to study the regulation and expression of I(Ca,L) in human atrial myocytes and in HL-1 cells. Basal I(Ca,L) was reduced in AF compared to sinus rhythm (SR) controls, mRNA and protein levels of the pore-forming alpha1C subunit of L-type Ca2+ channel (LCC alpha1C) 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 I(Ca,L) amplitudes, while mouse rMIF (20 or 40 nM, 24 h) suppressed peak I(Ca,L) in HL-1 cells by approximately 69% and approximately 83% in a concentration-dependent manner. Mouse rMIF impaired the time-dependent recovery from inactivation of I(Ca,L) and down-regulated LCC alpha1C subunit levels. The depression of I(Ca,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 I(Ca,L) amplitudes through impairment of channel function, down-regulation of LCC alpha1C subunit levels, and the activation of c-Src kinases in atrial myocytes.
Rao
Fang
F
Department of Cardiology, Guangdong Cardiovascular Institute, 96 Dongchuan Road, Guangzhou 510080, PR China.
Deng
Chun-Yu
CY
Wu
Shu-Lin
SL
Xiao
Ding-Zhang
DZ
Yu
Xi-Yong
XY
Kuang
Su-Juan
SJ
Lin
Qiu-Xiong
QX
Shan
Zhi-Xin
ZX
D000328:Adult; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019061:src-Family Kinases / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D008263:Macrophage Migration-Inhibitory Factors; D019061:src-Family Kinases