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 Ca(2+) currents (IC a,L ), T-type Ca(2+) currents (IC a,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 IC a,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 IC a,T, shifted the inactivation curve to the left. These results suggest that TNF-α is involved in the pathogenesis of AF, probably via decreasing IC a,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.
Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.|Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Fang
F
Rao
Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Yu-Mei
YM
Xue
Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Wei
W
Wei
Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Hui
H
Yang
Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Fang-Zhou
FZ
Liu
Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Shao-Xian
SX
Chen
Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Su-Juan
SJ
Kuang
Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Jie-Ning
JN
Zhu
Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.|Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Shu-Lin
SL
Wu
Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou, China.|Research Centre of Medical Sciences, Guangdong General Hospital, Guangzhou, China.|Guangdong Academy of Medical Sciences, Guangzhou, China.
Chun-Yu
CY
Deng
D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D014409:Tumor Necrosis Factor-alpha
HL-1 cells; T-type Ca2+ channel; atrial fibrillation; tumour necrosis factor-α