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Vol. 93, No. 1-2, 2014
Issue release date: March 2014
Pharmacology 2014;93:69-75

Anti-Inflammatory Activity of Ezetimibe by Regulating NF-κB/MAPK Pathway in THP-1 Macrophages

Qin L. · Yang Y.-B. · Yang Y.-X. · Zhu N. · Li S.-X. · Liao D.-F. · Zheng X.-L.
aDivision of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, and bThe Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, and cInstitute of Pharmacy and Pharmacology, South China University, and dThe Second Affiliated Hospital, South China University, Hengyang, Hunan, China; eMatthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, Western University, London, Ont., and fSmooth Muscle Research Group, Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Calgary, Alta., Canada

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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. © 2014 S. Karger AG, Basel

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