title: FK866 compromises mitochondrial metabolism and adaptive stress responses in cultured cardiomyocytes.
abstract: OBJECTIVE
  FK866 is an inhibitor of the NAD(+) synthesis rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Using FK866 to target NAD(+) synthesis has been proposed as a treatment for inflammatory diseases and cancer. However, use of FK866 may pose cardiovascular risks, as NAMPT expression is decreased in various cardiomyopathies, with low NAD(+) levels playing an important role in cardiovascular disease progression. In addition, low NAD(+) levels are associated with cardiovascular risk conditions such as aging, dyslipidemia, and type II diabetes mellitus. The aim of this work was to study the effects of FK866-induced NAD(+) depletion on mitochondrial metabolism and adaptive stress responses in cardiomyocytes.
  
  
  RESULTS
  FK866 was used to deplete NAD(+) levels in cultured rat cardiomyocytes. Cell viability, mitochondrial metabolism, and adaptive responses to insulin, norepinephrine, and H2O2 were assessed in cardiomyocytes. The drop in NAD(+) induced by FK866 decreased mitochondrial metabolism without changing cell viability. Insulin-stimulated Akt phosphorylation, glucose uptake, and H2O2-survival were compromised by FK866. Glycolytic gene transcription was increased, whereas cardiomyocyte hypertrophy induced by norepinephrine was prevented. Restoring NAD(+) levels via nicotinamide mononucleotide administration reestablished mitochondrial metabolism and adaptive stress responses.
  
  
  CONCLUSIONS
  This work shows that FK866 compromises mitochondrial metabolism and the adaptive response of cardiomyocytes to norepinephrine, H2O2, and insulin.
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Alejandra P
authors: AP
authors: Oyarzún
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Francisco
authors: F
authors: Westermeier
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Christian
authors: C
authors: Pennanen
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Camila
authors: C
authors: López-Crisosto
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Valentina
authors: V
authors: Parra
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Cristian
authors: C
authors: Sotomayor-Flores
authors: Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Gina
authors: G
authors: Sánchez
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Zully
authors: Z
authors: Pedrozo
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile. Electronic address: rtroncoso@inta.uchile.cl.
authors: Rodrigo
authors: R
authors: Troncoso
authors: Advanced Center for Chronic Disease (ACCDiS) and Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: slavander@uchile.cl.
authors: Sergio
authors: S
authors: Lavandero
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide; D007328:Insulin / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D000178:Acrylamides; D016207:Cytokines; D007328:Insulin; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D009243:NAD; D009537:Nicotinamide Mononucleotide; D006861:Hydrogen Peroxide; D054409:Nicotinamide Phosphoribosyltransferase; C504970:nicotinamide phosphoribosyltransferase, rat; D009638:Norepinephrine
keywords: Adaptive response; FK866 (PubChem CID: 6914657); Heart; Metabolism; Mitochondria; NAD(+); Nicotinamide mononucleotide (PubChem CID: 14180)