Mechanism of macrophage migration inhibitory factor‐induced decrease of T‐type Ca²⁺ channel current in atrium‐derived cells

Abstract

New findings What is the central question of this study? Recent evidence indicates that T‐type calcium channels may play an important role in the pathogenesis of atrial fibrillation. We previously reported that macrophage migration inhibitory factor (MIF), a pro‐inflammatory cytokine, reduced L‐type calcium channel expression in atrial fibrillation. The role of MIF in the regulation of atrial T‐type calcium channels has not been previously investigated. What is the main finding and its importance? In the present study, we report that MIF decreases the T‐type calcium current in atrium‐derived myocytes through impairment of channel function and activation of c‐Src kinases, representing a potential pathogenic mechanism in atrial fibrillation. The T‐type Ca 2+ current ( I Ca,T ) plays an important role in the pathogenesis of atrial fibrillation (AF). The present study sought to investigate the role of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, in the regulation of T‐type Ca 2+ channels (TCCs) in atrial myocytes. We used the whole‐cell voltage‐clamp technique and biochemical assays to study the regulation and expression of I Ca,T in atrial myocytes. Gene levels of the α1G and α1H subunit of TCCs were decreased in human atrial tissue of patients with AF. In cultured atrium‐derived myocytes (HL‐1 cells), mouse recombinant MIF (20 or 40 n m , 24 h) suppressed peak I Ca,T in a concentration‐dependent manner, impaired the voltage‐dependent activation of I Ca,T and downregulated TCC α1G and α1H mRNA. The Src inhibitors genistein and PP1 significantly enhanced I Ca,T . The reduction of I Ca,T and TCC subunit mRNA induced by recombinant MIF could be reversed by genistein and PP1. The TCC α1G associated with Src in HL‐1 cells and mouse cardiomycytes. Macrophage migration inhibitory factor is involved in the pathogenesis of AF, probably by decreasing the T‐type calcium current in atrium‐derived myocytes through impairment of channel function and activation of c‐Src kinases, representing a potential pathogenic mechanism in atrial fibrillation.