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:
Carotid artery; atherosclerosis; inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / pharmacology*
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Atherosclerosis / drug therapy*
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Atherosclerosis / enzymology
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Atherosclerosis / genetics
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Atherosclerosis / immunology
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Atherosclerosis / pathology
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Carotid Arteries / drug effects*
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Carotid Arteries / enzymology
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Carotid Arteries / immunology
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Carotid Arteries / pathology
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Carotid Artery Diseases / drug therapy*
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Carotid Artery Diseases / enzymology
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Carotid Artery Diseases / genetics
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Carotid Artery Diseases / immunology
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Carotid Artery Diseases / pathology
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Cells, Cultured
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Chemokine CXCL1 / metabolism*
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Collagen / metabolism
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Cytokines / antagonists & inhibitors*
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Cytokines / metabolism
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Diet, High-Fat
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology*
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / enzymology
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Human Umbilical Vein Endothelial Cells / immunology
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Humans
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophil Infiltration / drug effects*
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
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Nicotinamide Phosphoribosyltransferase / metabolism
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Piperidines / pharmacology*
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Plaque, Atherosclerotic*
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Signal Transduction / drug effects
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Time Factors
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Transcription Factor RelA / metabolism
Substances
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Acrylamides
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Anti-Inflammatory Agents
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Apolipoproteins E
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CXCL1 protein, human
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Chemokine CXCL1
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Cxcl1 protein, mouse
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Cytokines
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Enzyme Inhibitors
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N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
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Piperidines
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RELA protein, human
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Transcription Factor RelA
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Collagen
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human
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nicotinamide phosphoribosyltransferase, mouse
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse