title: Inhibition of Glutathione Production Induces Macrophage CD36 Expression and Enhances Cellular-oxidized Low Density Lipoprotein (oxLDL) Uptake.
abstract: The glutathione (GSH)-dependent antioxidant system has been demonstrated to inhibit atherosclerosis. Macrophage CD36 uptakes oxidized low density lipoprotein (oxLDL) thereby facilitating foam cell formation and development of atherosclerosis. It remains unknown if GSH can influence macrophage CD36 expression and cellular oxLDL uptake directly. Herein we report that treatment of macrophages with l-buthionine-S,R-sulfoximine (BSO) decreased cellular GSH production and ratios of GSH to glutathione disulfide (GSH/GSSG) while increasing production of reactive oxygen species. Associated with decreased GSH levels, macrophage CD36 expression was increased, which resulted in enhanced cellular oxLDL uptake. In contrast, N-acetyl cysteine and antioxidant enzyme (catalase or superoxide dismutase) blocked BSO-induced CD36 expression as well as oxLDL uptake. In vivo, administration of mice with BSO increased CD36 expression in peritoneal macrophages and kidneys. BSO had no effect on CD36 mRNA expression and promoter activity but still induced CD36 protein expression in macrophages lacking peroxisome proliferator-activated receptor γ expression, suggesting it induced CD36 expression at the translational level. Indeed, we determined that BSO enhanced CD36 translational efficiency. Taken together, our study demonstrates that cellular GSH levels and GSH/GSSG status can regulate macrophage CD36 expression and cellular oxLDL uptake and demonstrate an important anti-atherogenic function of the GSH-dependent antioxidant system by providing a novel molecular mechanism.
authors.affiliation: From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: From the State Key Laboratory of Medicinal Chemical Biology, Medicine, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China and.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Colleges of Life Sciences and.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Colleges of Life Sciences and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Colleges of Life Sciences and.
authors.forename: Xingzhe
authors.initials: X
authors.lastname: Ma
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shengzhong
authors.initials: S
authors.lastname: Duan
authors.affiliation: Colleges of Life Sciences and.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Medicinal Chemical Biology, Medicine.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China and jihonghan2008@nankai.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: From the State Key Laboratory of Medicinal Chemical Biology, Colleges of Life Sciences and yajunduan@nankai.edu.cn.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000493:pharmacokinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000963:Antimetabolites; D018955:CD36 Antigens; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D019328:Buthionine Sulfoximine; D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine
keywords: CD36; antioxidant; atherosclerosis; foam cell; glutamate-cysteine ligase; glutathione; macrophage; peroxisome proliferator-activated receptor (PPAR); translation regulation