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

• Published in: Acta pharmacologica Sinica Vol. 44; no. 1; pp. 58 - 70
• Main Authors: Huang, Zhu-qi, Luo, Wu, Li, Wei-xin, Chen, Pan, Wang, Zhe, Chen, Rui-jie, Wang, Yi, Huang, Wei-jian, Liang, Guang
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.01.2023; Nature Publishing Group
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apolipoprotein E; Apolipoproteins E; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Biomedical and Life Sciences; Biomedicine; Diet, High-Fat - adverse effects; High fat diet; I-kappa B Kinase - metabolism; Immunology; Inflammation - drug therapy; Inflammation - metabolism; Inflammatory diseases; Internal Medicine; Macrophages; Medical Microbiology; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; NF-κB protein; Pharmacology/Toxicology; Phosphorylation; Sesquiterpenes - pharmacology; Sesquiterpenes - therapeutic use; Signal transduction; Vaccine; atherosclerosis; IKK; NF-κB; costunolide; IKKβ; inflammation
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-022-00928-0

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. 10 μM) 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 IKKβ as 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.