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Published on: April 3, 2017
Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages
Simona Stavri1, Violeta G Trusca1, Maya Simionescu1
1Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.
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.
Insights
Metformin, an anti-diabetic drug, improves apolipoprotein E (apoE) levels in macrophages under inflammatory stress by inhibiting NF-κB. This finding suggests metformin
Area of Science:
- Cardiovascular Research
- Immunology
- Pharmacology
Background:
- Macrophage-derived apolipoprotein E (apoE) plays a key role in preventing atherosclerosis.
- Inflammatory stress reduces apoE expression in macrophages, worsening the condition.
- Metformin, an anti-diabetic medication, exhibits anti-inflammatory properties and vascular protection.
Purpose of the Study:
- To investigate the effect of metformin on macrophage apoE expression.
- To determine if metformin influences apoE levels under normal and lipopolysaccharide (LPS)-induced inflammatory conditions.
Main Methods:
- Assessed metformin's impact on apoE expression in macrophages.
- Investigated metformin's effect on LPS-induced inflammation and apoE regulation.
- Examined the role of NF-κB signaling pathway in LPS-mediated apoE downregulation.
Main Results:
- Metformin slightly increased apoE expression at high doses (5-10 mM).
- Low doses of metformin (1-3 mM) mitigated LPS-induced reduction in apoE expression.
- LPS-induced NF-κB binding to the apoE gene's regulatory elements (ME.2 and promoter) downregulated apoE.
- Metformin inhibited NF-κB nuclear translocation, thereby enhancing apoE levels during inflammation.
Conclusions:
- Metformin modulates macrophage apoE expression, particularly under inflammatory stress.
- By inhibiting NF-κB, metformin preserves apoE levels, offering potential therapeutic benefits.
- Metformin's safety, low cost, and efficacy in inflammatory states position it as a potential adjuvant therapy for atherosclerosis.
