Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice
| Autor: | Inga Bauer, Sébastien Lenglet, Fabrizio Montecucco, Sabine Steffens, Franco Patrone, Nicolas Vuilleumier, Graziano Pelli, Fabienne Burger, Nikolaos Stergiopulos, Alessandra Quercioli, Rodrigo A. Fraga-Silva, Rafaela F. da Silva, Maria Bertolotto, Irene Caffa, Franco Dallegri, Sara Vazquez Calvo, Robson A.S. Santos, Mathias Fabre, Alessio Nencioni, François Mach, Katia Galan, Alberto Ballestrero, Santina Bruzzone, Mirko Magnone, Giovanna Sociali |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Carotid Artery Diseases
0301 basic medicine Piperidines/pharmacology Time Factors Chemokine CXCL1 Transcription Factor RelA/metabolism Anti-Inflammatory Agents Nicotinamide phosphoribosyltransferase Pharmacology Mice chemistry.chemical_compound 0302 clinical medicine Piperidines Signal Transduction/drug effects Neutrophil Infiltration/drug effects Anti-Inflammatory Agents/pharmacology Enzyme Inhibitors Nicotinamide Phosphoribosyltransferase Apolipoproteins E/deficiency/genetics Cells Cultured ddc:616 Enzyme Inhibitors/pharmacology Mice Knockout Cytokines/antagonists & inhibitors/metabolism Hematology Plaque Atherosclerotic 3. Good health CXCL1 Carotid Arteries Matrix Metalloproteinase 9 Neutrophil Infiltration Carotid Arteries/drug effects/enzymology/immunology/pathology Cytokines Collagen Matrix Metalloproteinase 9/metabolism medicine.symptom Infiltration (medical) Atherosclerosis/drug therapy/enzymology/genetics/immunology/pathology Signal Transduction Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors/metabolism Inflammation Acrylamides/pharmacology Diet High-Fat Chemokine CXCL1/metabolism 03 medical and health sciences Apolipoproteins E In vivo Collagen/metabolism Human Umbilical Vein Endothelial Cells medicine Animals Humans ddc:576 Acrylamides business.industry Transcription Factor RelA Carotid Artery Diseases/drug therapy/enzymology/genetics/immunology/pathology Human Umbilical Vein Endothelial Cells/drug effects/enzymology/immunology medicine.disease In vitro Mice Inbred C57BL Disease Models Animal 030104 developmental biology chemistry inflammation Ischaemic myocardium Immunology atherosclerosis business Neutrophil recruitment Carotid artery 030217 neurology & neurosurgery |
| Zdroj: | Thrombosis and Haemostasis; Vol 111 Thrombosis and Haemostasis, Vol. 111, No 2 (2014) pp. 308-322 Thrombosis and Haemostasis Thrombosis and haemostasis |
| ISSN: | 2567-689X 0340-6245 |
| Popis: | SummaryPharmacological 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|