Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10751471 | Biochemical and Biophysical Research Communications | 2015 | 6 Pages |
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 5â²-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.
Keywords
cox2DNAPTFIIDMPMphorbol 12-myristate 13-acetateIFN-γCD36AMPKiNOSLUCTNFαFBSNF-κBLPSDMEMcAMPDulbecco's modified Eagle MediumPMAp38 MAPKCyclic adenosine monophosphateApoeapolipoprotein Esodium dodecyl sulphate-polyacrylamide gel electrophoresisSDS-PAGEinterleukintumour necrosis factor alphacluster of differentiation 36hoursfoetal calf seruminducible nitric oxide synthasecyclooxygenase 2nuclear factor kappa-light-chain-enhancer of activated B cellsluciferaselipopolysaccharideMacrophagesMurine peritoneal macrophagesMetforminp38 mitogen-activated protein kinaseInterferon gamma
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Authors
Simona Stavri, Violeta G. Trusca, Maya Simionescu, Anca V. Gafencu,