title: Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction.
abstract: OBJECTIVE
  Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed.
  
  
  RESULTS
  Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD(+)-dependent deacetylase in the production of this chemokine.
  
  
  METHODS
  The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction.
  
  
  CONCLUSIONS
  Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice.
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland. fabrizio.montecucco@unige.ch
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Inga
authors.initials: I
authors.lastname: Bauer
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Timo
authors.initials: T
authors.lastname: Speer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Elena
authors.initials: E
authors.lastname: Mannino
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Katia
authors.initials: K
authors.lastname: Galan
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.forename: Anna
authors.initials: A
authors.lastname: Garuti
authors.forename: Christophe
authors.initials: C
authors.lastname: Montessuit
authors.forename: René
authors.initials: R
authors.lastname: Lerch
authors.forename: Corinne
authors.initials: C
authors.lastname: Pellieux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Mage
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastian
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Angèle
authors.initials: A
authors.lastname: Gayet-Ageron
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage*; D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D009243:NAD / Q000096:biosynthesis; D020556:Neutrophil Infiltration / Q000187:drug effects*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000178:Acrylamides; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D017382:Reactive Oxygen Species; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase