5-Aminoimidazole-4-Carboxamide-1-β-4-Ribofuranoside Inhibits Proinflammatory Response in Glial Cells: A Possible Role of AMP-Activated Protein Kinase

Giri, Shailendra; Nath, Narendra; Smith, Brian A.; Viollet, Benoı̂t; Singh, Avtar; Singh, Inderjit

doi:10.1523/jneurosci.4288-03.2004

Cited by 256 publications

(238 citation statements)

References 46 publications

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“…tion in vascular endothelial cells as well as in other type of cells [9,10]. In the present study, we showed that AICAR suppresses cytokine-induced NF-κB activation, leading to inhibition of proinflammatory genes.…”

Section: Discussionsupporting

confidence: 59%

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

et al. 2010

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Aims/hypothesis Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells. Methods Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor κB (NF-κB) activation was assessed by reporter gene assay. Results Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokineinduced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-κB activation. We therefore examined the effect of liraglutide on TNFα-induced NF-κB activation and NF-κB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-κB activation and TNFα-induced IκB degradation. It also reduced TNFα-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-κB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP. Conclusions/interpretation Liraglutide exerts an antiinflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-κB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.

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Section: Discussionsupporting

confidence: 59%

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

et al. 2010

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“…It has been reported that AICAR attenuates lipopolysaccharide-induced activation of NF-B via downregulation of IkB kinase ␣/␤ activity in glial cells. 16 This is the same mechanism as we showed in vascular endothelial cells, suggesting that AMPK activation may inhibit cytokineinduced NF-B activation by suppressing IKK activity.…”

Section: Discussionsupporting

confidence: 75%

Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells

et al. 2006

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Abstract-AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor B (NF-B) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-␣-induced NF-B activation and TNF-␣-induced IB kinase activity. Furthermore, metformin attenuated the TNF-␣-induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-␣-and interleukin-1␤-induced NF-B reporter gene expression. AICAR also suppressed the TNF-␣-and interleukin-1␤-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPK␣1 attenuated metformin or AICAR-induced inhibition of NF-B activation by TNF-␣, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-B activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.

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“…However, still the mechanism by which AICAR decrease cytokine levels warrants further investigations. In glial cells AICAR induced activation of AMPK has been shown to inhibit expression of pro-inflammatory cytokines by attenuation of nuclear factor-κB activation (NF-κB) and nuclear translocation of NF-κB (Giri et al, 2004). Given that AICAR activates AMPK in both adipose tissue (Lihn et al, 2004;Sell et al, 2006) and in skeletal muscle (Merrill et al, 1997;Buhl et al, 2001), activation of AMPK followed by inhibition of the NF-κB pathway might be the major mechanism whereby AICAR affects cytokine gene expression and production.…”

Section: Discussionmentioning

confidence: 99%

The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells

Lihn

Pedersen

Lund

et al. 2008

Molecular and Cellular Endocrinology

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5-Aminoimidazole-4-Carboxamide-1-β-4-Ribofuranoside Inhibits Proinflammatory Response in Glial Cells: A Possible Role of AMP-Activated Protein Kinase

Abstract: AMP-activated protein kinase (AMPK) is

Cited by 256 publications

References 46 publications

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells

The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells

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