title: Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice.
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.
authors.affiliation: Dr. Alessio Nencioni, MD, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy, Tel.: +39 010 353 8990, Fax: +39 010 353 8945, E-mail: alessio.nencioni@unige.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.forename: Rafaela F
authors.initials: RF
authors.lastname: da Silva
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Fraga-Silva
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.forename: Mathias
authors.initials: M
authors.lastname: Fabre
authors.forename: Inga
authors.initials: I
authors.lastname: Bauer
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.forename: Mirko
authors.initials: M
authors.lastname: Magnone
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sociali
authors.forename: Alessandra
authors.initials: A
authors.lastname: Quercioli
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.forename: Katia
authors.initials: K
authors.lastname: Galan
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Sara
authors.initials: S
authors.lastname: Vázquez Calvo
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.forename: Robson A
authors.initials: RA
authors.lastname: Santos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Stergiopulos
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
authors.affiliation: Dr. Fabrizio Montecucco, MD, PhD, Cardiology Division, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, 64 Avenue Roseraie, 1211 Geneva, Switzerland, Tel.: +41 22 382 72 38, Fax: +41 22 382 72 45, E-mail: Fabrizio.montecucco@unige.ch.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000178:Acrylamides; D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; C498143:RELA protein, human; D051996:Transcription Factor RelA; D003094:Collagen; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C495867:nicotinamide phosphoribosyltransferase, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Carotid artery; atherosclerosis; inflammation