The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction
The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction
复制标题
选择性 NLRP3 炎症小体抑制剂 MCC950 可减少心肌梗塞小鼠模型中的心肌纤维化并改善心脏重塑。
DOI：
10.1016/j.intimp.2019.04.022
复制
发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Tang, Yanhua
中科院分区：
文献类型：
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作者：
Gao, Rifeng;Shi, Huairui;Tang, Yanhua
背景/目的是心肌梗死（MI）后的炎症反应（MI）可能会增加心肌纤维化和随后的心脏重塑。先前发现MCC950是一种特定的NLRP3抑制剂，可有效抑制炎症因子IL-18和IL-1β的释放。在这项研究中，我们使用实验小鼠模型评估了MCC950作为MI的潜在新治疗策略，对心肌纤维化和心脏重塑的影响。方法：雄性C57BL/6小鼠受到左冠状动脉结扎型MI和MI和MI和MI和MI和MI和然后用MCC950（10 mg/kg）或PBS处理14天。 30天后，进行超声心动图以评估心脏功能，并使用H＆E-E-和Masson的三色染色切片评估心肌纤维化。通过蛋白质印迹，免疫荧光，ELISA和实时定量PCR分析炎症因子和纤维化标志物的心肌表达：10 mg/kg组的射血分数（40.7 +//- 4.2％；与对照组（14.0 +/- 4.4％）相比，= 0.0029）在统计上保留。 MCC950处理的动物也降低了心肌纤维化（MCC950，23.2 +/- 3.0 vs PBS，36.2 +/- 3.7; p <0.05）。此外，在MCC950治疗的动物中，心肌NLRP3，切割IL-1β和IL-18水平降低。 H＆E和分子检查显示，心脏中炎症细胞浸润和炎症因子表达的降低。在体外，MCC950抑制了NLRP3，CASPASE-1活性降低，进一步下调IL-1β和IL-18。结论：作为特定的NLRP3抑制剂，MCC950可以通过抑制早期炎症模型中的纤维化并改善心脏功能MI之后的回应。
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-1 beta. 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-1 beta, 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-1 beta 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.