Acute administration of tumour necrosis factor-alpha induces spontaneous calcium release via the reactive oxygen species pathway in atrial myocytes

作者：Zuo, Song; Li, Lin-ling; Ruan, Yan-fei; Jiang, Le; Li, Xin; Li, Song-nan; Wen, Song-nan; Bai, Rong; Liu, Nian; Du, Xin; Dong, Jian-zeng; Ma, Chang-Sheng^*

来源：Europace, 2018, 20(8): 1367-1374.

DOI：10.1093/europace/eux271

• Inflammation
• Atrial fibrillation
• Tumour necrosis factor-alpha
• Calcium signalling
• Reactive oxygen species
• Calcium/calmodulin-dependent protein kinase II

Aims The arrhythmogenic mechanisms of atrial fibrillation (AF) that are induced by acute inflammation, such as postoperative AF, are not well understood. We investigated the acute effects of tumour necrosis factor-alpha (TNF-alpha) that mimic acute inflammation on Ca2+ handling in isolated atrial myocytes and its underlying mechanisms.
Methods and results Cytosol Ca2+ handling and mitochondrial reactive oxygen species (ROS) production were studied in freshly isolated atrial myocytes of wild-type mice that were exposed to TNF-alpha (0.05 ng/mL) for 2 h by lonoptix and confocal microscopy. The acute effects of TNF-alpha on Ca2+ handling were decreased amplitudes and prolonged decay times of Ca2+ transients in isolated atrial myocytes. A significant reduction in the sarcoplasmic reticulum (SR) Ca2+ content was detected in TNF-alpha treated cells, which was associated with increased spontaneous Ca2+ release events. In particular, physiological concentrations of TNF-alpha dramatically promoted the frequency of spontaneous Ca2+ waves and Ca2+ sparks, while the spark mass presented with reduced amplitudes and prolonged durations. The underlying mechanisms of pro-arrhythmic effects of TNF-alpha were further investigated. Acute exposure to TNF-alpha rapidly promoted mitochondrial ROS production that was correlated with the acute effect of TNF-alpha on Ca2+ handling, and enhanced the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) and the phosphorylation of RyR2 However, the performance of ROS inhibitor, DL-Dithiothreitol (DTT), reversed Ca2+ handling disorders induced by TNF-alpha.
Conclusion Tumour necrosis factor-alpha rapidly increases spontaneous Ca2+ release and promotes atrial arrhythmogenesis via the ROS pathway, which suggests that antioxidant therapy is a promising strategy for acute inflammation related AF.

• 出版日期2018-8
• 单位首都医科大学; 首都医科大学附属北京安贞医院