The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction induced myocardial fibrosis and cardiac remodeling in mice

• Published in: International immunopharmacology 2021-01, Vol.90, p.107133-107133, Article 107133
• Main Authors: Gao, Ri-Feng, Li, Xiao, Xiang, Hai-Yan, Yang, Heng, Lv, Chun-Yu, Sun, Xiao-Lei, Chen, Hong-Zhang, Gao, Yang, Yang, Jue-Sheng, Luo, Wei, Yang, Yi-Qing, Tang, Yan-Hua
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Cardiac function; Cardiac remodeling; Cells, Cultured; Coronary artery; Covalence; Disease Models, Animal; Diterpenes, Kaurane - pharmacology; Enzyme-linked immunosorbent assay; Fibrosis; Furans; Heart; Heart attacks; Heart function; Heterocyclic Compounds, 4 or More Rings - pharmacology; IL-1β; Immunofluorescence; Indenes; Inflammasomes; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Inflammation; Inflammatory response; Inhibitors; Interleukin 18; Interleukin-1beta - metabolism; Leukocytes (neutrophilic); Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Myocardial fibrosis; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neutrophil Infiltration - drug effects; Neutrophils - drug effects; Neutrophils - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inhibitor; Oridonin; Polymerase chain reaction; Receptors, Interleukin-18 - metabolism; Signal Transduction; Stroke Volume - drug effects; Sulfonamides; Sulfones - pharmacology; Thiazolidines - pharmacology; Thiones - pharmacology; Ventricle; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.107133

•Oridonin, as well as MCC950 and CY-09, inhibits the NLRP3 inflammasome response.•Oridonin, found in traditional Chinese medicine, shows anti-inflammatory property in mice MI model.•Oridonin treatment reduces myocardial fibrosis and preserves cardiac function after MI. Myocardial infarction (MI) triggers a strong inflammatory response that is associated with myocardial fibrosis and cardiac remodeling. Interleukin (IL)-1β and IL-18 are key players in this response and are controlled by NLRP3-inflammatory bodies. Oridonin is a newly reported NLRP3 inhibitor with strong anti-inflammatory activity. We hypothesized that the covalent NLRP3 inhibitor Oridonin could reduce IL-1β and IL-18 expression and ameliorate myocardial fibrosis after myocardial infarction in mice, improve poor heart remodeling, and preserve heart function. Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with Oridonin (1, 3, or 6 mg/kg), MCC950 (10 mg/kg), CY-09 (5 mg/kg) or saline three times a week for two weeks. Four weeks after MI, cardiac function and myocardial fibrosis were assessed. In addition, myocardial expressions of inflammatory factors and fibrotic markers were analyzed by western blot, immunofluorescence, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. Oridonin treatment preserved left ventricular ejection fraction and fractional shortening, and markedly limited the myocardial infarct size in treated mice. The myocardial fibrosis was lower in the 1 mg/kg group (15.98 ± 1.64)%, 3 mg/kg group (17.39 ± 2.45)%, and 6 mg/kg group (16.76 ± 3.06)% compared to the control group (23.38 ± 1.65)%. Moreover, similar with the results of Oridonin, MCC950 and CY-09 also preserved cardiac function and reduced myocardial fibrosis. The expression levels of NLRP3, IL-1β and IL-18 were decreased in the Oridonin treatment group compared to non-treated group. In addition, myocardial macrophage and neutrophil influxes were attenuated in the Oridonin treated group. The covalent NLRP3-inflammasome inhibitor Oridonin reduces myocardial fibrosis and preserves cardiac function in a mouse MI model, which indicates potential therapeutic effect of Oridonin on acute MI patients.