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Title: Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages

Abstract

The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis. - Highlights: • High doses of metformin slightly increase apoE expression in macrophages. • Low doses of metforminmore » up-regulate apoE gene in endotoxin-stressed macrophages. • Metformin reduces the negative effect of LPS on apoE expression by NF-κB inhibition.« less

Authors:
; ; ;
Publication Date:
OSTI Identifier:
22462066
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 461; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETATES; AMP; ARTERIOSCLEROSIS; DOSES; DRUGS; ELECTROPHORESIS; GELS; GENES; INFLAMMATION; INHIBITION; INTERFERON; LUCIFERASE; MACROPHAGES; NECROSIS; PROMOTERS; SAFETY; STRESSES; TRANSCRIPTION FACTORS; VISIBLE RADIATION

Citation Formats

Stavri, Simona, Trusca, Violeta G., Simionescu, Maya, and Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro. Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.04.057.
Stavri, Simona, Trusca, Violeta G., Simionescu, Maya, & Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro. Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages. United States. doi:10.1016/J.BBRC.2015.04.057.
Stavri, Simona, Trusca, Violeta G., Simionescu, Maya, and Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro. Fri . "Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages". United States. doi:10.1016/J.BBRC.2015.04.057.
@article{osti_22462066,
title = {Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages},
author = {Stavri, Simona and Trusca, Violeta G. and Simionescu, Maya and Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro},
abstractNote = {The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5–10 mM). Low doses of metformin (1–3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5′-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis. - Highlights: • High doses of metformin slightly increase apoE expression in macrophages. • Low doses of metformin up-regulate apoE gene in endotoxin-stressed macrophages. • Metformin reduces the negative effect of LPS on apoE expression by NF-κB inhibition.},
doi = {10.1016/J.BBRC.2015.04.057},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 461,
place = {United States},
year = {2015},
month = {5}
}