title: Inhibition of macrophage-derived foam cell formation by ezetimibe via the caveolin-1/MAPK pathway.
abstract: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol, but its effect on atherosclerosis is unclear. Foam cell formation has been implicated as a key mediator during the development of atherosclerosis. The purpose of this study was to investigate the effects of ezetimibe on foam cell formation and explore the underlying mechanism. The results presented here show that ezetimibe reduces atherosclerotic lesions in apolipoprotein E deficient (apoE-/-) mice by lowering cholesterol levels. Treatment of macrophages with Chol:MβCD resulted in foam cell formation, which was concentration-dependently inhibited by the presence of ezetimibe. Mechanically, ezetimibe treatment downregulated the expression of CD36 and scavenger receptor class B1 (SR-B1), but upregulated the expression of apoE and caveolin-1 in macrophage-derived foam cells, which kept consistent with our microarray results. Moreover, treatment with ezetimibe abrogated the increase of phospho-extracellular signal regulated kinase (ERK) 1/2 and their nuclear accumulation in foam cells. Inhibition of the MAPK pathway by the MEK inhibitor PD98059 attenuated the inhibitory effect of ezetimibe on the expression of p-ERK1/2 and caveolin-1. Taken together, these results showed that ezetimibe suppressed foam cell formation via the caveolin-1/MAPK signalling pathway, suggesting that inhibition of foam cell formation might be a novel mechanism underlying the anti-atherosclerotic effect of ezetimibe.
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.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.|Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, Western University, London, Canada.
authors.forename: Yun-Bo
authors.initials: YB
authors.lastname: Yang
authors.affiliation: Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, Western University, London, Canada.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Yang
authors.affiliation: The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Neng
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Ya-Guang
authors.initials: YG
authors.lastname: Ni
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Shun-Xiang
authors.initials: SX
authors.lastname: Li
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.|Department of Biochemistry & Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Zheng
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy; D018955:CD36 Antigens / Q000235:genetics; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D000069438:Ezetimibe / Q000494:pharmacology* / Q000627:therapeutic use; D005487:Foam Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D051242:Caveolin 1; D002784:Cholesterol; D000069438:Ezetimibe
keywords: MAPK; atherosclerosis; caveolin-1; ezetimibe; foam cell