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

Alessio Nencioni, Rafaela F. da Silva, Rodrigo A. Fraga-Silva, 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 DallegriRobson A S Santos, Nikolaos Stergiopulos, François Mach, Nicolas Vuilleumier, Fabrizio Montecucco

Research output: Contribution to journalArticle

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 phosphoribosyltrans-ferase (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-KB 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.

Original languageEnglish
Pages (from-to)308-322
Number of pages15
JournalThrombosis and Haemostasis
Volume111
Issue number2
DOIs
Publication statusPublished - Nov 7 2013

Keywords

  • Atherosclerosis
  • Carotid artery
  • Inflammation

ASJC Scopus subject areas

  • Hematology

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    Nencioni, A., da Silva, R. F., Fraga-Silva, R. A., Steffens, S., Fabre, M., Bauer, I., Caffa, I., Magnone, M., Sociali, G., Quercioli, A., Pelli, G., Lenglet, S., Galan, K., Burger, F., Calvo, S. V., Bertolotto, M., Bruzzone, S., Ballestrero, A., Patrone, F., ... Montecucco, F. (2013). Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice. Thrombosis and Haemostasis, 111(2), 308-322. https://doi.org/10.1160/th13-07-0531