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Titles listNicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated...
Titles listNicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated...
Professional Article
unige:78054 
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Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice |
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| Published in | Thrombosis and Haemostasis. 2014, vol. 111, no. 2, p. 308-322 | |
| Abstract | Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability. | |
| Keywords | Acrylamides/pharmacology — Animals — Anti-Inflammatory Agents/pharmacology — Apolipoproteins E/deficiency/genetics — Atherosclerosis/drug therapy/enzymology/genetics/immunology/pathology — Carotid Arteries/drug effects/enzymology/immunology/pathology — Carotid Artery Diseases/drug therapy/enzymology/genetics/immunology/pathology — Cells, Cultured — Chemokine CXCL1/metabolism — Collagen/metabolism — Cytokines/antagonists & inhibitors/metabolism — Diet, High-Fat — Disease Models, Animal — Enzyme Inhibitors/pharmacology — Human Umbilical Vein Endothelial Cells/drug effects/enzymology/immunology — Humans — Matrix Metalloproteinase 9/metabolism — Mice — Mice, Inbred C57BL — Mice, Knockout — Neutrophil Infiltration/drug effects — Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors/metabolism — Piperidines/pharmacology — Plaque, Atherosclerotic — Signal Transduction/drug effects — Time Factors — Transcription Factor RelA/metabolism | |
| Identifiers | DOI: 10.1160/TH13-07-0531 PMID: 24196571 | |
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| Research groups | L'athérosclérose et ses complications cliniques (591) Chimie et protéomique clinique (270) | |
| Citation (ISO format) | NENCIONI, Alessio et al. Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice. In: Thrombosis and Haemostasis, 2014, vol. 111, n° 2, p. 308-322. doi: 10.1160/TH13-07-0531 https://archive-ouverte.unige.ch/unige:78054 |
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