title: Anti-inflammatory activity of ezetimibe by regulating NF-κB/MAPK pathway in THP-1 macrophages.
abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are involved in the inflammatory process during atherogenesis. Here, we performed daily gavage of ezetimibe in apolipoprotein E-deficient mice fed with a high-fat diet and found that ezetimibe administration decreased the level of C-reactive protein significantly. To investigate the potential molecular mechanism, we employed microarray analysis on the cultured macrophages treated with Chol:MβCD in the presence or absence of ezetimibe. We found that ezetimibe dramatically down-regulated the expression of the tumor necrosis factor-α (TNF-α) gene. Consistent with the microarray results, TNF-α protein levels were inhibited by ezetimibe. Moreover, ezetimibe suppressed the promoter activity of TNF-α but not TNF-α lacking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) binding domain in THP-1 cells treated with phorbol myristate acetate and Chol:MβCD. Furthermore, treatment of THP-1 macrophages with ezetimibe resulted in the degradation of IκB and subsequently inhibited nuclear translocation of NF-κB and its transcriptional activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway using PD98059 attenuated the reduction effect of ezetimibe on the expression of NF-κB. Collectively, our results demonstrated that the anti-inflammatory properties of ezetimibe in THP-1 macrophages are, at least in part, through suppression of NF-κB activation via the MAPK pathway. These data provide direct evidence for the potential application of ezetimibe in the prevention and treatment of inflammatory diseases.
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Yun-Bo
authors.initials: YB
authors.lastname: Yang
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Yang
authors.forename: Neng
authors.initials: N
authors.lastname: Zhu
authors.forename: Shun-Xiang
authors.initials: SX
authors.lastname: Li
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001384:Azetidines / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000032:analysis; D002460:Cell Line; D000069438:Ezetimibe; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D001384:Azetidines; D016328:NF-kappa B; D002097:C-Reactive Protein; D020928:Mitogen-Activated Protein Kinases; D000069438:Ezetimibe