Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China.
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Int Immunopharmacol. 2019 Sep;74:105575. doi: 10.1016/j.intimp.2019.04.022. Epub 2019 Jul 9.
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.
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.
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.
MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.
背景/目的：心肌梗死后（MI）的早期炎症反应可能会增加心肌纤维化和随后的心脏重构。MCC950 是一种特异性 NLRP3 抑制剂，先前已被发现可有效抑制炎症因子 IL-18 和 IL-1β 的释放。在这项研究中，我们使用实验性小鼠模型评估 MCC950（一种潜在的新 MI 治疗策略）对心肌纤维化和心脏重构的影响。
雄性 C57BL/6 小鼠接受左冠状动脉结扎以诱导 MI，然后用 MCC950（10mg/kg）或 PBS 治疗 14 天。30 天后，进行超声心动图检查以评估心功能，并用 H&E 和 Masson 三色染色切片评估心肌纤维化。通过 Western blot、免疫荧光、ELISA 和实时定量 PCR 分析心肌中炎症因子和纤维化标志物的表达。
与对照组（14.0±4.4%）相比，10mg/kg 组的射血分数（40.7±4.2%；N=6，p=0.0029）在统计学上得到保存。在 MCC950 治疗的动物中，心肌纤维化也减少（MCC950，23.2±3.0 与 PBS，36.2±3.7；p<0.05）。此外，MCC950 治疗的动物中 NLRP3、切割的 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减少。体外，MCC950 抑制 NLRP3，降低 caspase-1 活性，进一步下调 IL-1β 和 IL-18。
作为一种特异性 NLRP3 抑制剂，MCC950 通过抑制 MI 后早期炎症反应，可减轻纤维化并改善小鼠模型的心脏功能。
