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Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice

Nencioni, Alessio
da Silva, Rafaela F
Fraga-Silva, Rodrigo A
Bauer, Inga
Caffa, Irene
Magnone, Mirko
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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/pharmacologyAnimalsAnti-Inflammatory Agents/pharmacologyApolipoproteins E/deficiency/geneticsAtherosclerosis/drug therapy/enzymology/genetics/immunology/pathologyCarotid Arteries/drug effects/enzymology/immunology/pathologyCarotid Artery Diseases/drug therapy/enzymology/genetics/immunology/pathologyCells, CulturedChemokine CXCL1/metabolismCollagen/metabolismCytokines/antagonists & inhibitors/metabolismDiet, High-FatDisease Models, AnimalEnzyme Inhibitors/pharmacologyHuman Umbilical Vein Endothelial Cells/drug effects/enzymology/immunologyHumansMatrix Metalloproteinase 9/metabolismMiceMice, Inbred C57BLMice, KnockoutNeutrophil Infiltration/drug effectsNicotinamide Phosphoribosyltransferase/antagonists & inhibitors/metabolismPiperidines/pharmacologyPlaque, AtheroscleroticSignal Transduction/drug effectsTime FactorsTranscription Factor RelA/metabolism
PMID: 24196571
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Research groups Chimie et protéomique clinique (270)
L'athérosclérose et ses complications cliniques (591)
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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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Deposited on : 2015-12-02

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