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

• DOI: 10.1160/th13-07-0531
• Publication Date: 2013-11-07T08:29:57Z
• Authors: Rafaela F. da Silva; Rodrigo A. Fraga-...; Sabine Steffens; Mathias Fabre; Inga Bauer; Irene Caffa; Mirko Magnone; Giovanna Sociali; Alessandra Quercioli; Graziano Pelli; Sébastien Lenglet; Katia Galan; Fabienne Burger; Sara Vázquez Calvo; Maria Bertolotto; Santina Bruzzone; Alberto Ballestrero; Franco Patrone; Franco Dallegri; Robson A. S. Santos; Nikolaos Stergiop...; François Mach; Nicolas Vuilleumier; Fabrizio Montecucco; Alessio Nencioni
• Keywords: Nicotinamide phosphoribosyltransferase; CXCL1; Arteriogenesis; CXCL2; Infiltration (HVAC)

Summary Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation 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 recently found to reduce ischaemic myocardium, would exert beneficial effects in mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation ApoE-/- mice were fed Western-type diet. FK866 or vehicle administrated intraperitoneally from week 8 until 11 of Treatment reduced infiltration MMP-9 content increased collagen levels compared vehicle. No effect on other histological parameters, including intraplaque lipids macrophages, observed. These findings reduction both systemic CXCL1 FK866-treated mice. In vitro, did not affect release neutrophils, but it strongly production endothelial cells which, vivo model, identified as main source at level. synthesis inhibition appears reflect interference nuclear factor-κB signalling shown p65 pre-treated FK866. conclusion, pharmacological NAMPT activity mitigates inflammation reducing CXCL1-mediated activities neutrophils. results support further assessments inhibitors potential prevention vulnerability.