Document Detail

Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction.
MedLine Citation:
PMID:  22452634     Owner:  NLM     Status:  MEDLINE    
AIMS: 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.
INNOVATION: 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.
Fabrizio Montecucco; Inga Bauer; Vincent Braunersreuther; Santina Bruzzone; Alexander Akhmedov; Thomas F Lüscher; Timo Speer; Alessandro Poggi; Elena Mannino; Graziano Pelli; Katia Galan; Maria Bertolotto; Sébastien Lenglet; Anna Garuti; Christophe Montessuit; René Lerch; Corinne Pellieux; Nicolas Vuilleumier; Franco Dallegri; Jacqueline Mage; Carlos Sebastian; Raul Mostoslavsky; Angèle Gayet-Ageron; Franco Patrone; François Mach; Alessio Nencioni
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-14
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  18     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-06-19     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  630-41     Citation Subset:  IM    
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MeSH Terms
Acrylamides / administration & dosage*
Chemokine CXCL2 / metabolism
Myocardial Infarction* / drug therapy,  enzymology,  pathology
Myocardial Reperfusion Injury / drug therapy,  pathology
NAD / biosynthesis
Neutrophil Infiltration / drug effects*
Nicotinamide Phosphoribosyltransferase* / antagonists & inhibitors,  metabolism
Oxidative Stress / drug effects
Piperidines / administration & dosage*
Reactive Oxygen Species / metabolism
Signal Transduction
Reg. No./Substance:
0/Acrylamides; 0/Chemokine CXCL2; 0/Cxcl2 protein, mouse; 0/N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; 0/Piperidines; 0/Reactive Oxygen Species; 0U46U6E8UK/NAD; EC Phosphoribosyltransferase

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