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

作者：Nencioni Alessio; da Silva Rafaela F; Fraga Silva Rodrigo A; Steffens Sabine; Fabre Mathias; Bauer Inga; Caffa Irene; Magnone Mirko; Sociali Giovanna; Quercioli Alessandra; Pelli Graziano; Lenglet Sebastien; Galan Katia; Burger Fabienne; Calvo Sara Vazquez; Bertolotto Maria; Bruzzone Santina; Ballestrero Alberto; Patrone Franco; Dallegri Franco; Santos Robson A S; Stergiopulos Nikolaos; Mach Francois; Vuilleumier Nicolas; Montecucco Fabrizio^*

来源：Thrombosis and Haemostasis, 2014, 111(2): 308-322.

DOI：10.1160/TH13-07-0531

• Carotid artery
• inflammation
• atherosclerosis

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-kappa B 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.

• 出版日期2014-2