GTS-21 alleviates sepsis-induced atrial fibrillation susceptibility by modulating macrophage polarization and Neuregulin-1 secretion

作者：Jiabao Zhou, Keke Wu, Yingxu Ma, Jiayi Zhu, Yong Zhou, Zixi Zhang, Fanqi Li, Gaoming Zeng, Shunyi Li, Siyuan Tan, Yusha Zhang, Cancan Wan, Tao Tu, Qiuzhen Lin, Qiming Liu · 发表于：International Immunopharmacology · 年份：2025 · DOI：10.1016/j.intimp.2025.114561 · 被引用次数：20 · 研究领域：Cardiac Fibrosis and Remodeling、Atrial Fibrillation Management and Outcomes、Immune cells in cancer

OBJECTIVE: Sepsis-induced atrial fibrillation (AF) is driven by systemic inflammation and macrophage-mediated atrial remodeling, with proinflammatory M1 macrophages playing a key role. This study investigates whether GTS-21, an α7nAChR agonist, can reduce AF susceptibility by promoting macrophage polarization towards the anti-inflammatory M2 phenotype. METHODS: A mouse model of lipopolysaccharide (LPS) (10 mg/kg)-induced sepsis was used to explore the relationship between atrial inflammation and AF. GTS-21 (20 mg/kg) was administered to assess its impact on 48-h survival and AF incidence. Cardiac function was evaluated using echocardiography. Markers of myocardial injury, including CK-MB, LDH, and cTnI, were measured. Macrophage polarization and atrial inflammation were assessed using immunofluorescence, flow cytometry, RT-qPCR, and western blotting. Oxidative stress and mitochondrial function were evaluated using reactive oxygen species (ROS) measurements, electron microscopy, and mitochondrial protein expression analysis. Calcium dynamics were studied using western blotting and confocal microscopy. RESULTS: In LPS-induced septic mice, GTS-21 improved 48-h survival rates and reduced the induction rate and duration of AF (P < 0.05). Echocardiography showed a preserved left ventricular ejection fraction and enhanced diastolic function. Mechanistically, it promoted M2 macrophage polarization, inhibited the NF-κB P65/NLRP3/C-caspase 1 pathway to reduce IL-1β release, and allevia...