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: Xiaoxiao Yang, Hui Yao, Yuanli Chen, Lei Sun, Yan Li, Xingzhe Ma, Shengzhong Duan, Xiaoju Li, Rong Xiang, Jihong Han, Yajun Duan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 36 Pg. 21788-99 (Sep 04 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26187465 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antimetabolites
• CD36 Antigens
• Free Radical Scavengers
• Lipoproteins, LDL
• PPAR gamma
• Reactive Oxygen Species
• oxidized low density lipoprotein
• Buthionine Sulfoximine
• Glutathione
• Glutathione Disulfide
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antimetabolites (pharmacology)
• Blotting, Western
• Buthionine Sulfoximine (pharmacology)
• CD36 Antigens (genetics, metabolism)
• Cell Line
• Free Radical Scavengers (pharmacology)
• Gene Expression (drug effects)
• Glutathione (antagonists & inhibitors, biosynthesis, metabolism)
• Glutathione Disulfide (metabolism)
• Lipoproteins, LDL (metabolism, pharmacokinetics)
• Macrophages (drug effects, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR gamma (genetics, metabolism)
• Protein Biosynthesis (drug effects, genetics)
• RNA Interference
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction