Zhou Jiabao, Wu Keke, Ma Yingxu, Zhu Jiayi, Zhou Yong, Zhang Zixi, Li Fanqi, Zeng Gaoming, Li Shunyi, Tan Siyuan, Zhang Yusha, Wan Cancan, Tu Tao, Lin Qiuzhen, Liu Qiming
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China; Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province, Changsha, Hunan 410011, PR China; Cardiovascular Disease Research Center of Hunan Province, Changsha, Hunan 410011, PR China; Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan 410011, PR China.
First Clinical College, Changsha Medical University, Changsha, Hunan 410219, PR China.
Int Immunopharmacol. 2025 May 8;154:114561. doi: 10.1016/j.intimp.2025.114561. Epub 2025 Apr 5.
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.
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.
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 alleviated oxidative stress. Additionally, mitochondrial structure was restored by reversing fission and promoting fusion, while calcium-handling proteins (NCX-1, RYR2, and SERCA2a) were regulated to prevent intracellular calcium overload, reducing AF susceptibility.
GTS-21 mitigated atrial inflammation and reduced the incidence of AF in mice with sepsis by regulating macrophage polarization, reducing oxidative stress, and preserving mitochondrial and calcium dynamics in cardiomyocytes. These findings highlight the therapeutic potential of GTS-21 in treating sepsis-induced AF.
脓毒症诱导的心房颤动（AF）由全身炎症和巨噬细胞介导的心房重塑驱动，促炎M1巨噬细胞起关键作用。本研究调查α7烟碱型乙酰胆碱受体（α7nAChR）激动剂GTS-21是否可通过促进巨噬细胞向抗炎M2表型极化来降低AF易感性。
使用脂多糖（LPS）（10mg/kg）诱导的脓毒症小鼠模型来探究心房炎症与AF之间的关系。给予GTS-21（20mg/kg）以评估其对48小时生存率和AF发生率的影响。使用超声心动图评估心脏功能。测量心肌损伤标志物，包括肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）和心肌肌钙蛋白I（cTnI）。使用免疫荧光、流式细胞术、逆转录-定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法评估巨噬细胞极化和心房炎症。使用活性氧（ROS）测量、电子显微镜和线粒体蛋白表达分析评估氧化应激和线粒体功能。使用蛋白质免疫印迹法和共聚焦显微镜研究钙动力学。
在LPS诱导的脓毒症小鼠中，GTS-21提高了48小时生存率，降低了AF的诱导率和持续时间（P<0.05）。超声心动图显示左心室射血分数得以保留且舒张功能增强。机制上，它促进M2巨噬细胞极化，抑制核因子κB P65/核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）/半胱天冬酶1（C-caspase 1）通路以减少白细胞介素-1β（IL-1β）释放，并减轻氧化应激。此外，通过逆转裂变并促进融合来恢复线粒体结构，同时调节钙处理蛋白（钠钙交换体1（NCX-1）、兰尼碱受体2（RYR2）和肌浆网钙ATP酶2a（SERCA2a））以防止细胞内钙超载，降低AF易感性。
GTS-21通过调节巨噬细胞极化、降低氧化应激以及维持心肌细胞中的线粒体和钙动力学，减轻了脓毒症小鼠的心房炎症并降低了AF发生率。这些发现突出了GTS-21在治疗脓毒症诱导的AF方面的治疗潜力。
