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

   
@article{APS10739,
	author = {Zhu-qi Huang and Wu Luo and Wei-xin Li and Pan Chen and Zhe Wang and Rui-jie Chen and Yi Wang and Wei-jian Huang and Guang Liang},
	title = {Costunolide alleviates atherosclerosis in high-fat diet-fed ApoE−/− mice through covalently binding to IKKβ and inhibiting NF-κB-mediated inflammation},
	journal = {Acta Pharmacologica Sinica},
	volume = {44},
	number = {1},
	year = {2022},
	keywords = {},
	abstract = {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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10739}
}