Costunolide alleviates atherosclerosis in high-fat diet-fed ApoE^(−/−) mice through covalently binding to IKKβ and inhibiting NF-κB-mediated inflammation  

作　　者：Zhu-qi Huang Wu Luo Wei-xin Li Pan Chen Zhe Wang Rui-je Chen Yi Wang Weijian Huang Guang Liang 

机构地区：[1]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China [2]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,311399,China [3]Department of Cardiology and Medical Research Center,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325035,China [4]Department of Pharmacy,the Second Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China

出　　处：《Acta Pharmacologica Sinica》2023年第1期58-70,共13页中国药理学报（英文版）

基　　金：This study was supported by National Natural Science Foundation of China (21961142009 to GL,82000793 to WL,81900331 to ZW);Zhejiang Provincial Key Scientific Project (2021C03041 to GL).

摘　　要：Costunolide(CTD)is a sesquiterpene lactone isolated from costus root and exhibits various biological activities including anti-inflammation.Since atherosclerosis is a chronic inflammatory disease,we herein investigated the anti-atherosclerotic effects of CTD and the underlying mechanism.Atherosclerosis was induced in ApoE−/−mice by feeding them with a high-fat diet(HFD)for 8 weeks,followed by administration of CTD(10,20 mg·kg^(−1)·d^(−1),i.g.)for 8 weeks.We showed that CTD administration dose-dependently alleviated atherosclerosis in HFD-fed ApoE^(−/−)mice.Furthermore,we found that CTD dose-dependently reduced inflammatory responses in aortas of the mice,as CTD prevented infiltration of inflammatory cells in aortas and attenuated oxLDL uptake in macrophages,leading to reduced expression of pro-inflammatory and pro-fibrotic molecules in aortas.Similar results were observed in oxLDL-stimulated mouse primary peritoneal macrophages(MPMs)in vitro.We showed that pretreatment with CTD(2.5,5.10μM)restrained oxLDL-induced inflammatory responses in MPMs by blocking pro-inflammatory NF-κB/p65 signaling pathway.We further demonstrated that CTD inactivated NF-κB via covalent binding to cysteine 179 on IKKβ,a canonical upstream regulator of NF-κB,reducing its phosphorylation and leading to conformational change in the active loop of IKKβ.Our results discover IKKβas the target of CTD for its anti-inflammatory activity and elucidate a molecular mechanism underlying the anti-atherosclerosis effect of CTD.CTD is a potentially therapeutic candidate for retarding inflammatory atherosclerotic diseases.

关 键 词：ATHEROSCLEROSIS COSTUNOLIDE INFLAMMATION IKK NF-ΚB IKKΒ 

分 类 号：R59[医药卫生—内科学]