Yue-Wei Li1, Si-Xu Chen2,3,4, Ying Yang2,3,4, Zeng-Hui Zhang2,3,4, Wei-Bin Zhou2,3,4, Yu-Na Huang2,3,4, Zhao-Qi Huang2,3,4, Jia-Qi He2,3,4, Ting-Feng Chen2,3,4, Jing-Feng Wang5,6,7, Zhao-Yu Liu8, Yang-Xin Chen9,10,11. 1. Department of Respiratory Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. 2. Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China. 3. Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong Province, Guangzhou, China. 4. Guangzhou Key Laboratory of Molecular Mechanism and Translation in Major Cardiovascular Disease, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 5. Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China. wjingf@mail.sysu.edu.cn. 6. Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong Province, Guangzhou, China. wjingf@mail.sysu.edu.cn. 7. Guangzhou Key Laboratory of Molecular Mechanism and Translation in Major Cardiovascular Disease, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. wjingf@mail.sysu.edu.cn. 8. Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. liuzhy98@mail.sysu.edu.cn. 9. Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China. chenyx39@mail.sysu.edu.cn. 10. Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong Province, Guangzhou, China. chenyx39@mail.sysu.edu.cn. 11. Guangzhou Key Laboratory of Molecular Mechanism and Translation in Major Cardiovascular Disease, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. chenyx39@mail.sysu.edu.cn.
Abstract
PURPOSE: Colchicine, a multipotent anti-inflammatory drug, has been reported to alleviate cardiac remodeling and improve cardiac function after acute myocardial infarction (AMI). However, the underlying mechanism remains incompletely understood. Because neutrophils extracellular traps (NETs) enhance inflammation and participate in myocardial ischemia injury, and colchicine can inhibit NETosis, we thus aimed to determine whether colchicine exerts cardioprotective effects on AMI via suppressing NETs. METHODS: Adult C57BL/6 mice were subjected to permanent ligation of the left anterior descending coronary artery and treated with colchicine (0.1 mg/kg/day) or Cl-amidine (10 mg/kg/day) for 7 or 28 days after AMI. Cardiac function was evaluated by echocardiography, and NETs detected by immunofluorescence. ROS production was detected using 2',7'-dichlorodihydrofluorescein diacetates (DCFH-DA) fluorometry. Intracellular Ca2+ concentration was assessed by a fluorometric ratio technique. RESULTS: We found that colchicine treatment significantly increased mice survival (89.8% in the colchicine group versus 67.9% in control, n = 32 per group; log-rank test, p < 0.05) and improved cardiac function at day 7 (left ventricular ejection fraction (LVEF): 28.0 ± 9.2% versus 12.6 ± 3.9%, n = 8 per group; p < 0.001) and at day 28 (LVEF: 26.2 ± 7.2% versus 14.8 ± 6.7%, n = 8 per group; p < 0.001) post-AMI. In addition, the administration of colchicine inhibited NETs formation and inflammation. Furthermore, colchicine inhibited NETs formation by reducing NOX2/ROS production and Ca2+ influx. Moreover, prevention of NETs formation with Cl-amidine significantly alleviated AMI-induced cardiac remodeling. CONCLUSIONS: Colchicine inhibited NETs and cardiac inflammation, and alleviated cardiac remodeling after acute myocardial infarction.
PURPOSE: Colchicine, a multipotent anti-inflammatory drug, has been reported to alleviate cardiac remodeling and improve cardiac function after acute myocardial infarction (AMI). However, the underlying mechanism remains incompletely understood. Because neutrophils extracellular traps (NETs) enhance inflammation and participate in myocardial ischemia injury, and colchicine can inhibit NETosis, we thus aimed to determine whether colchicine exerts cardioprotective effects on AMI via suppressing NETs. METHODS: Adult C57BL/6 mice were subjected to permanent ligation of the left anterior descending coronary artery and treated with colchicine (0.1 mg/kg/day) or Cl-amidine (10 mg/kg/day) for 7 or 28 days after AMI. Cardiac function was evaluated by echocardiography, and NETs detected by immunofluorescence. ROS production was detected using 2',7'-dichlorodihydrofluorescein diacetates (DCFH-DA) fluorometry. Intracellular Ca2+ concentration was assessed by a fluorometric ratio technique. RESULTS: We found that colchicine treatment significantly increased mice survival (89.8% in the colchicine group versus 67.9% in control, n = 32 per group; log-rank test, p < 0.05) and improved cardiac function at day 7 (left ventricular ejection fraction (LVEF): 28.0 ± 9.2% versus 12.6 ± 3.9%, n = 8 per group; p < 0.001) and at day 28 (LVEF: 26.2 ± 7.2% versus 14.8 ± 6.7%, n = 8 per group; p < 0.001) post-AMI. In addition, the administration of colchicine inhibited NETs formation and inflammation. Furthermore, colchicine inhibited NETs formation by reducing NOX2/ROS production and Ca2+ influx. Moreover, prevention of NETs formation with Cl-amidine significantly alleviated AMI-induced cardiac remodeling. CONCLUSIONS: Colchicine inhibited NETs and cardiac inflammation, and alleviated cardiac remodeling after acute myocardial infarction.
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