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

• DOI: 10.1016/j.intimp.2025.114561
• Publication Date: 2025-04-07T06:00:52Z
• Authors: 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
• Keywords: neuregulin 1; Neuregulin; Macrophage polarization

Sepsis-induced atrial fibrillation (AF) is driven by systemic inflammation and macrophage-mediated remodeling, with proinflammatory M1 macrophages playing a key role. This study investigates whether GTS-21, an α7nAChR agonist, can reduce AF susceptibility promoting macrophage polarization towards the anti-inflammatory M2 phenotype. A mouse model of lipopolysaccharide (LPS) (10 mg/kg)-induced sepsis was used to explore relationship between AF. GTS-21 (20 mg/kg) administered assess its impact on 48-h survival incidence. Cardiac function evaluated using echocardiography. Markers myocardial injury, including CK-MB, LDH, cTnI, were measured. Macrophage assessed immunofluorescence, flow cytometry, RT-qPCR, western blotting. Oxidative stress mitochondrial reactive oxygen species (ROS) measurements, electron microscopy, protein expression analysis. Calcium dynamics studied blotting confocal microscopy. In LPS-induced septic mice, improved rates reduced induction rate duration (P < 0.05). Echocardiography showed preserved left ventricular ejection fraction enhanced diastolic function. Mechanistically, it promoted polarization, inhibited NF-κB P65/NLRP3/C-caspase 1 pathway IL-1β release, alleviated oxidative stress. Additionally, structure restored reversing fission fusion, while calcium-handling proteins (NCX-1, RYR2, SERCA2a) regulated prevent intracellular calcium overload, reducing susceptibility. mitigated incidence in mice regulating stress, preserving cardiomyocytes. These findings highlight therapeutic potential treating sepsis-induced