Rifeng Gao1, Huairui Shi2, Suchi Chang2, Yang Gao2, Xiao Li2, Chunyu Lv1, Heng Yang1, Haiyan Xiang1, Juesheng Yang1, Lei Xu3, Yanhua Tang4. 1. Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China. 2. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. 3. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: xu.lei2@zs-hospitai.sh.cn. 4. Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China. Electronic address: tyh6565@163.com.
Abstract
BACKGROUND/AIMS: Early inflammatory responses after myocardial infarction (MI) are likely to increase myocardial fibrosis and subsequent cardiac remodeling. MCC950, a specific NLRP3 inhibitor, was previously found to effectively inhibit the release of inflammatory factors IL-18 and IL-1β. In this study, we evaluated the effect of MCC950, as a potential new treatment strategy for MI, on myocardial fibrosis and cardiac remodeling using an experimental mouse model. METHODS: Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with MCC950 (10 mg/kg) or PBS for 14 days. After 30 days, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E- and Masson's Trichrome-stained sections. Myocardial expression of inflammatory factors and fibrosis markers was analyzed by western blotting, immunofluorescence, ELISA, and real-time quantitative PCR. RESULTS: The ejection fraction in the 10 mg/kg group (40.7 ± 4.2%; N = 6, p = 0.0029) was statistically preserved compared to that in the control group (14.0 ± 4.4%). Myocardial fibrosis was also reduced in MCC950-treated animals (MCC950, 23.2 ± 3.0 vs PBS, 36.2 ± 3.7; p < 0.05). Moreover, myocardial NLRP3, cleaved IL-1β, and IL-18 levels were reduced in MCC950-treated animals. H&E and molecular examination revealed decreases in inflammatory cell infiltration and inflammatory factor expression in the heart. In vitro, MCC950 inhibited NLRP3, reduced caspase-1 activity, and further downregulated IL-1β and IL-18. CONCLUSION: MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.
BACKGROUND/AIMS: Early inflammatory responses after myocardial infarction (MI) are likely to increase myocardial fibrosis and subsequent cardiac remodeling. MCC950, a specific NLRP3 inhibitor, was previously found to effectively inhibit the release of inflammatory factors IL-18 and IL-1β. In this study, we evaluated the effect of MCC950, as a potential new treatment strategy for MI, on myocardial fibrosis and cardiac remodeling using an experimental mouse model. METHODS: Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with MCC950 (10 mg/kg) or PBS for 14 days. After 30 days, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E- and Masson's Trichrome-stained sections. Myocardial expression of inflammatory factors and fibrosis markers was analyzed by western blotting, immunofluorescence, ELISA, and real-time quantitative PCR. RESULTS: The ejection fraction in the 10 mg/kg group (40.7 ± 4.2%; N = 6, p = 0.0029) was statistically preserved compared to that in the control group (14.0 ± 4.4%). Myocardial fibrosis was also reduced in MCC950-treated animals (MCC950, 23.2 ± 3.0 vs PBS, 36.2 ± 3.7; p < 0.05). Moreover, myocardial NLRP3, cleaved IL-1β, and IL-18 levels were reduced in MCC950-treated animals. H&E and molecular examination revealed decreases in inflammatory cell infiltration and inflammatory factor expression in the heart. In vitro, MCC950 inhibited NLRP3, reduced caspase-1 activity, and further downregulated IL-1β and IL-18. CONCLUSION: MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.