Contributors: Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A); Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS); Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Signalisation et physiopathologie cardiovasculaire (UMRS1180); Institut National de la Santé et de la Recherche Médicale (INSERM); Phénotypage du petit animal (UMS28); Université Pierre et Marie Curie - Paris 6 (UPMC); Détoxication et réparation tissulaire; Université de Rennes 1 (UR1); Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM); Laboratoire de Photophysique et Photochimie Supramoléculaires et Macromoléculaires (PPSM); École normale supérieure - Cachan (ENS Cachan)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS); Centre de Recherche Cardiovasculaire de Lariboisiere; Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM); This study was supported by the Association Française contre les Myopathies (AFM N 16282), the Agence Nationale de la Recherche (ANR) grant NAD-Heart ANR-17-CE17-0015-01 and ANR-08-GENOPAT-038, Fondation de France grant 00075811 and fundings from Institut National pour la Santé Et la Recherche Médicale (INSERM), Center National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie Paris 6, and University Paris Sud. Drs Diguet and Tannous, and Mr Deloux were supported by a PhD fellowship of French Ministère de la Recherche et de l’Enseignement Supérieur. Dr Diguet was further supported by a 1-year PhD fellowship from AFM. Dr Brenner is supported by the Roy J. Carver Trust. GGL is supported by a Wellcome Trust Senior Fellowship (104612/Z/14/Z).; The authors thank V. Veksler and R. Ventura-Clapier (Inserm UMR-S 1180) for expert advice on respiration assays, Luc Bertrand (UCL, Belgium) for expert advice on AMPK detection, A. Angelini (UMR 8256) for technical help in these assays, A. Grosfeld (UMR 8256) for preliminary setup experiments for Nmrk2 cloning, Florence Lefebvre for adult rat cardiomyocyte isolation.; ANR-17-CE17-0015,NAD-HEART,Supplémentation en précurseur du NAD+ pour le traitement de l'insuffisance cardiaque(2017); ANR-08-GENO-0038,REMODEL-SRF,Remodelage des organes creux musculaires et dilatations: établir un lien avec le Facteur de Réponse au Sérum(2008)
نبذة مختصرة : Background: Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD + ) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD + in the failing heart. Methods: To explore possible alterations of NAD + homeostasis in the failing heart, we quantified the expression of NAD + biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF HKO ) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD + precursor supplementation on cardiac function in both mouse models. Results: We observed a 30% loss in levels of NAD + in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the Nmrk2 gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD + depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD + synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD + levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment. Conclusions: The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.
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