Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction

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 MageCarlos Sebastian, Raul Mostoslavsky, Angèle Gayet-Ageron, Franco Patrone, François MacH, Alessio Nencioni

Research output: Contribution to journalArticlepeer-review

Abstract

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. Antioxid. Redox Signal. 18, 630-641.

Original languageEnglish
Pages (from-to)630-641
Number of pages12
JournalAntioxidants and Redox Signaling
Volume18
Issue number6
DOIs
Publication statusPublished - Feb 20 2013

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

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