Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025
N-palmitoyl glycine mediates depression-associated atrial fibrillation via Man1a2-dependent autophagy and NRAP dysregulation.
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Chen Jiuling, Sheng Siqi, Zhang Jinhui, Li Yuchen, Jiang Tingting, Jiang Xiaohui, Li Jiahao, Lv Lin, Wang Zhiqi, Wei Yongkang, Fang Ning, Zhang Song, Yao Hong, Dong Yanghong, Xue Zheng, Dong Zengxiang, Liang Zhaoguang
Аннотация
AIMS: Although many large-scale clinical studies have confirmed that depression is an independent risk factor for atrial fibrillation (AF), the underlying mechanism remains unclear. This study aimed to investigate the pathogenesis of depression-associated AF.
METHODS AND RESULTS: The chronic unpredictable mild stress model of depression was established. In this model, we observed a significant increase in AF inducibility. In order to explore its potential mechanism, we analysed the serum metabolomics of humans and rats and the protein metabolomics of atrial tissue in rats. The levels of N-palmitoyl glycine in different tissues were quantified using liquid chromatography-mass spectrometry. Both in vivo and in vitro experiments were performed to validate the proposed mechanisms. Electrophysiological changes in isolated hearts were evaluated using the Langendorff perfusion system and multi-channel electrical mapping. Our findings suggest that N-palmitoyl glycine secreted by the white matter acts as a key factor in depression-associated AF. Both in vivo and in vitro experiments revealed that N-palmitoyl glycine reduces autophagy and the synthesis of nebulin-related anchoring protein in atrial myocytes by up-regulating α1,2-mannosidase expression. These changes lead to the intercalated disc rupture, a critical event in the pathogenesis of AF.
CONCLUSION: This study demonstrates that N-palmitoyl glycine plays a crucial role in the development of AF in the context of depression. These findings provide potential therapeutic targets for the prevention and treatment of AF following depression.
METHODS AND RESULTS: The chronic unpredictable mild stress model of depression was established. In this model, we observed a significant increase in AF inducibility. In order to explore its potential mechanism, we analysed the serum metabolomics of humans and rats and the protein metabolomics of atrial tissue in rats. The levels of N-palmitoyl glycine in different tissues were quantified using liquid chromatography-mass spectrometry. Both in vivo and in vitro experiments were performed to validate the proposed mechanisms. Electrophysiological changes in isolated hearts were evaluated using the Langendorff perfusion system and multi-channel electrical mapping. Our findings suggest that N-palmitoyl glycine secreted by the white matter acts as a key factor in depression-associated AF. Both in vivo and in vitro experiments revealed that N-palmitoyl glycine reduces autophagy and the synthesis of nebulin-related anchoring protein in atrial myocytes by up-regulating α1,2-mannosidase expression. These changes lead to the intercalated disc rupture, a critical event in the pathogenesis of AF.
CONCLUSION: This study demonstrates that N-palmitoyl glycine plays a crucial role in the development of AF in the context of depression. These findings provide potential therapeutic targets for the prevention and treatment of AF following depression.