Role of tumour necrosis factor‐a in the regulation of T‐type calcium channel current in HL‐1 cells

Increasing evidence indicates that inflammation contributes to the initiation and perpetuation of atrial fibrillation (AF). Although tumour necrosis factor (TNF)‐α levels are increased in patients with AF, the role of TNF‐α in the pathogenesis of AF remains unclear. Besides L‐type Ca²⁺ currents (I_Ca,L), T‐type Ca²⁺ currents (I_Ca,T) also plays an important role in the pathogenesis of AF. This study was designed to use the whole‐cell voltage‐clamp technique and biochemical assays to explore if TNF‐α is involved in the pathogenesis of AF through regulating I_Ca,T in atrial myocytes. It was found that compared with sinus rhythm (SR) controls, T‐type calcium channel (TCC) subunit mRNA levels were decreased, while TNF‐α expression levels were increased, in human atrial tissue from patients with AF. In murine atrial myocyte HL‐1 cells, after culturing for 24 h, 12.5, 25 and 50 ng/mL TNF‐α significantly reduced the protein expression levels of the TCC α1G subunit in a concentration‐dependent manner. The peak current was reduced by the application of 12.5 or 25 ng/mL TNF‐α in a concentration‐dependent manner (from ?15.08 ± 1.11 pA/pF in controls to ?11.89 ± 0.83 pA/pF and ?8.54 ± 1.55 pA/pF in 12.5 or 25 ng/mL TNF‐α group respectively). TNF‐α application also inhibited voltage‐dependent inactivation of I_Ca,T, shifted the inactivation curve to the left. These results suggest that TNF‐α is involved in the pathogenesis of AF, probably via decreasing I_Ca,T current density in atrium‐derived myocytes through impaired channel function and down‐regulation of channel protein expression. This pathway thus represents a potential pathogenic mechanism in AF.