Alejandra P Oyarzún1, Francisco Westermeier1, Christian Pennanen1, Camila López-Crisosto1, Valentina Parra1, Cristian Sotomayor-Flores1, Gina Sánchez2, Zully Pedrozo3, Rodrigo Troncoso4, Sergio Lavandero5. 1. 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. 2. Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile. 3. 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. 4. 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. 5. 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.
Abstract
AIM: 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. METHODS AND 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. CONCLUSION: This work shows that FK866 compromises mitochondrial metabolism and the adaptive response of cardiomyocytes to norepinephrine, H2O2, and insulin.
AIM: 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. METHODS AND 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. CONCLUSION: This work shows that FK866 compromises mitochondrial metabolism and the adaptive response of cardiomyocytes to norepinephrine, H2O2, and insulin.
Authors: Erin M Kropp; Katarzyna A Broniowska; Matthew Waas; Alyssa Nycz; John A Corbett; Rebekah L Gundry Journal: Stem Cells Transl Med Date: 2017-02-22 Impact factor: 6.940
Authors: Andrea Del Campo; Catalina Salamanca; Angelo Fajardo; Francisco Díaz-Castro; Catalina Bustos; Camila Calfío; Rodrigo Troncoso; Edgar R Pastene-Navarrete; Claudio Acuna-Castillo; Luis A Milla; Carlos A Villarroel; Francisco A Cubillos; Mario Aranda; Leonel E Rojo Journal: Molecules Date: 2021-10-12 Impact factor: 4.411
Authors: Barry E Kennedy; Michael Giacomantonio; J Patrick Murphy; Samuel Cutler; Maryanne Sadek; Prathyusha Konda; Joao A Paulo; Gopal P Pathak; Saskia H J Renkens; Stacy Grieve; Jonathan Pol; Steven P Gygi; Christopher Richardson; Daniel Gaston; Anthony Reiman; Guido Kroemer; Manal O Elnenaei; Shashi A Gujar Journal: Mol Ther Oncolytics Date: 2022-02-20 Impact factor: 7.200