The regulated in development and DNA damage response 2 (REDD2) gene mediates human monocyte cell death through a reduction in thioredoxin-1 expression |
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| Authors: | Jguirim-Souissi Imen Ludivine Billiet Clarisse Cuaz-Pérolin Nadège Michaud Mustapha Rouis |
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| Institution: | 1. Division of Structural Biology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Parel, Mumbai – 400012, India;2. ICMR Biomedical Informatics Centre, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Parel, Mumbai – 400012, India;1. Bone Metabolism Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy;2. Dept. of Pharmacology, Chemotherapy & Medical Toxicology, University of Milano, Italy;3. Orthopaedic Unit, San Raffaele Scientific Institute, Milano, Italy;4. IRCCS Istituto Ortopedico Galeazzi, Milano, Italy;1. Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea;2. Division of Wood Chemistry & Microbiology Department of Forest Products, Korea Forest Research Institute, Republic of Korea;3. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA;4. Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-050, Republic of Korea;5. Department of Microbiology, College of Medicine, Inje University, Busan 614-735, Republic of Korea |
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| Abstract: | In a previous study, we identified the regulated in development and DNA damage response 2 (REDD2) gene as a highly expressed gene in human atherosclerotic lesions in comparison to normal artery, as well as in cultured human macrophages, and showed its implication in oxidized low-density lipoprotein (LDL)-induced macrophage death sensitivity. In this article, we attempt to identify the mechanism by which REDD2 induces such a phenomenon. Transient transfection of U-937 monocytic cells with a pCI.CMV.REDD2 expression vector increased by approximately twofold the mRNA levels of REDD2 in comparison to control cells transfected with pCI.CMV.GFP. Reactive oxygen species (ROS) production was significantly induced in REDD2-transfected cells compared with control cells (157 ± 48 and 100 ± 8 arbitrary units/mg cell protein, respectively; p < 0.05). Moreover, a significant increase in parameters known to reflect the oxidative modifications of LDL was observed. Among enzymes involved in ROS production or degradation, we found a specific reduction in thioredoxin-1 (Trx-1) mRNA (～ 52 ± 7% decrease, p < 0.01 vs control cells) and protein (～ 60 ± 4% decrease, p < 0.001 vs control cells) levels in cells overexpressing REDD2 in comparison to control cells. In contrast, transfection of U-937 cells with siRNA against REDD2 decreased the mRNA levels of REDD2 by ～ 60% and increased Trx-1 mRNA and protein levels. Moreover, we observed no or a moderate increase in Bax (proapoptotic) and a significant decrease in Bcl2 (antiapoptotic) gene expression in cells that overexpress REDD2 compared to control cells. In addition, we showed that Trx-1 mRNA and protein levels were increased at low H2O2 doses and decreased at higher doses. Interestingly, macrophages isolated from human atherosclerotic lesions differentially express REDD2 and Trx-1. Indeed, in certain patients, levels of REDD2 mRNA were low and those of Trx-1 mRNA were high. In contrast, in other patients, levels of REDD2 were high and levels of Trx-1 mRNA were low. |
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