MCC950 attenuates doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis

被引：71
|
作者：
Zhang, Lei [1 ]
Jiang, Yue-Hua [1 ,2 ]
Fan, Cundong [3 ,4 ]
Zhang, Qian [1 ]
Jiang, Yong-Hao [5 ]
Li, Yan [5 ]
Xue, Yi-Tao [5 ]
机构：
[1] Shandong Univ Tradit Chinese Med, Clin Med Coll 1, Jinan 250000, Shandong, Peoples R China
[2] Shandong Univ Tradit Chinese Med, Affiliated Hosp, Cent Lab, Jinan 250000, Shandong, Peoples R China
[3] Shandong First Med Univ, Univ Shandong, Dept Neurol, Key Lab Cerebral Microcirculat, Tai An 271000, Shandong, Peoples R China
[4] Shandong Acad Med Sci, Tai An 271000, Shandong, Peoples R China
[5] Shandong Univ Tradit Chinese Med, Affiliated Hosp, Cardiovasc Dept, Jinan 250000, Shandong, Peoples R China
来源：
BIOMEDICINE & PHARMACOTHERAPY | 2021年 / 143卷
基金：
芬兰科学院; 中国国家自然科学基金;
关键词：
MCC950; Doxorubicin; Myocardial injury; NLRP3; inflammasome; Inflammatory; Pyroptosis; NLRP3; INFLAMMASOME; CANCER-THERAPY; CELL-DEATH; GSDMD; CARDIOTOXICITY; MECHANISM; CASPASES; CLEAVAGE;
D O I：
10.1016/j.biopha.2021.112133
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
MCC950, an NLRP3 inflammasome inhibitor, displays multiple pharmacological properties. However, the protective potential and underlying mechanism of MCC950 against doxorubicin (DOX)-induced myocardial injury has not been well investigated yet. Herein, DOX-induced myocardial injury in mice and in H9c2 myocardial cells was investigated, and the protective effects and underlying mechanism of MCC950 were fully explored. The results showed that MCC950 co-treatment significantly improved myocardial function, inhibited inflammatory and myocardial fibrosis, and attenuated cardiomyocyte pyroptosis in DOX-treated mice. Mechanismly, MCC950 had the potential to inhibit DOX-induced the cleavage of NLRP3, ASC, Caspase-1, IL-18, IL-1 beta and GSDMD in vivo. Moreover, MCC950 co-treatment in vivo suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis through the same molecular mechanism. Taken together, our findings validated that MCC950, an NLRP3 inflammasome inhibitor, has the potential to attenuate doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis.
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页数：12
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