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Europace. 2017 Oct 17. doi: 10.1093/europace/eux271. [Epub ahead of print]

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

Author information

1
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.

Abstract

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-α (TNF-α) 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-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.

Conclusion:

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.

KEYWORDS:

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

PMID:
29045723
DOI:
10.1093/europace/eux271

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