title: Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen: A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)γ-DEPENDENT MECHANISM.
abstract: Macrophage CD36 binds and internalizes oxidized low density lipoprotein (oxLDL) to facilitate foam cell formation. CD36 expression is activated by peroxisome proliferator-activated receptor γ (PPARγ). Tamoxifen, an anti-breast cancer medicine, has demonstrated pleiotropic functions including cardioprotection with unfully elucidated mechanisms. In this study, we determined that treatment of ApoE-deficient mice with tamoxifen reduced atherosclerosis, which was associated with decreased CD36 and PPARγ expression in lesion areas. At the cellular level, we observed that tamoxifen inhibited CD36 protein expression in human THP-1 monocytes, THP-1/PMA macrophages, and human blood monocyte-derived macrophages. Associated with decreased CD36 protein expression, tamoxifen reduced cellular oxLDL accumulation in a CD36-dependent manner. At the transcriptional level, tamoxifen decreased CD36 mRNA expression, promoter activity, and the binding of the PPARγ response element in CD36 promoter to PPARγ protein. Tamoxifen blocked ligand-induced PPARγ nuclear translocation and CD36 expression, but it increased PPARγ phosphorylation, which was due to that tamoxifen-activated ERK1/2. Furthermore, deficiency of PPARγ expression in macrophages abolished the inhibitory effect of tamoxifen on CD36 expression or cellular oxLDL accumulation both in vitro and in vivo Taken together, our study demonstrates that tamoxifen inhibits CD36 expression and cellular oxLDL accumulation by inactivating the PPARγ signaling pathway, and the inhibition of macrophage CD36 expression can be attributed to the anti-atherogenic properties of tamoxifen.
authors.affiliation: From the College of Life Sciences.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: the Institute of Translational Medicine, Nanchang University, Nanchang 330000.
authors.forename: Meixiu
authors.initials: M
authors.lastname: Jiang
authors.affiliation: the College of Biomedical Engineering, Hefei University of Technology, Hefei 230009, and School of Medicine, and.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the College of Life Sciences.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: From the College of Life Sciences.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the College of Life Sciences.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the College of Life Sciences.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.affiliation: From the College of Life Sciences.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: the Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shengzhong
authors.initials: S
authors.lastname: Duan
authors.affiliation: From the College of Life Sciences, the College of Biomedical Engineering, Hefei University of Technology, Hefei 230009, and the State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, hanjihong2015@hfut.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: From the College of Life Sciences, the College of Biomedical Engineering, Hefei University of Technology, Hefei 230009, and the State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, yduan@hfut.edu.cn.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D013629:Tamoxifen; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CD36; ERK1/2; PPARγ; atherosclerosis; cholesterol; lipoprotein metabolism; lipoprotein receptor; macrophage; tamoxifen