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Inhibition of Glutathione Production by L‐Buthionine‐(S,R)‐Sulfoximine Induces Macrophage CD36 Expression
Author(s) -
Yang Xiaoxiao,
Chen Yuanli,
Sun Lei,
Duan Yajun,
Han Jihong
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.763.7
Subject(s) - cd36 , glutathione , buthionine sulfoximine , foam cell , chemistry , reactive oxygen species , superoxide dismutase , antioxidant , oxidative stress , biochemistry , macrophage , microbiology and biotechnology , biology , enzyme , receptor , in vitro
Reduced glutathione (GSH) is a cytosolic antioxidant and reduces reactive oxygen species (ROS) by both enzymatic and non‐enzymatic reactions. The GSH‐dependent antioxidant system has been implicated in the development of atherosclerosis. Macrophage CD36 uptakes oxidized low‐density lipoprotein (oxLDL) thereby facilitating foam cell formation and lesion development. It remains unclear if cellular GSH levels can regulate CD36 expression and foam cell formation. Herein, we report that treatment of macrophages with L‐buthionine‐S,R‐sulfoximine (BSO) inhibited cellular GSH production, decreased cellular ratio of GSH to glutathione disulfide (GSH/GSSG), and increased ROS production. Associated with decreased GSH levels, macrophage CD36 expression was increased. BSO also induced foam cell formation in a CD36‐dependent manner. In contrast, N‐acetyl cysteine and antioxidant enzymes (catalase and superoxide dismutase) inhibited BSO‐induced CD36 expression and foam cell formation. In vivo , BSO increased CD36 expression in peritoneal macrophages and kidneys. BSO had little effect on CD36 mRNA expression and promoter activity indicating the induction occurred at the post‐transcriptional level. In addition, BSO induced CD36 expression in macrophages lacking PPARgamma expression. Furthermore, we determined that BSO had little effect on CD36 mRNA and protein stability but enhanced CD36 translational efficiency. Taken together, our study demonstrates that the GSH depletion induces macrophage CD36 expression and foam cell formation. The regulation of macrophage CD36 expression by cellular GSH levels and GSH/GSSG status supports the important role of GSH‐antioxidant system in the development of atherosclerosis.