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

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-α (TNF-α) that mimic acute inflammation on Ca²⁺ handling in isolated atrial myocytes and its underlying mechanisms.

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-α (0.05 ng/mL) for 2 h by Ionoptix and confocal microscopy. The acute effects of TNF-α 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-α treated cells, which was associated with increased spontaneous Ca²⁺ release events. In particular, physiological concentrations of TNF-α 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-α were further investigated. Acute exposure to TNF-α rapidly promoted mitochondrial ROS production that was correlated with the acute effect of TNF-α 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-α.

Tumour necrosis factor-α 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.