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Archives of cardiovascular diseases
Volume 109, n° 3
pages 207-215 (mars 2016)
Doi : 10.1016/j.acvd.2015.10.004
Received : 27 April 2015 ;  accepted : 9 October 2015
Nicotinamide adenine dinucleotide homeostasis and signalling in heart disease: Pathophysiological implications and therapeutic potential
Homéostasie et signalisation du nicotinamide adénine dinucléotide dans les pathologies cardiaques : implications physiopathologiques et potentiel thérapeutique

Figure 1

Figure 1 : 

Multiple roles of oxidized nicotinamide adenine dinucleotide (NAD+) in energy metabolism and cell signalling. A. Skeletal formula of NAD+ showing the site of reduction that gives rise to the reduced form (NADH) in oxidoreduction reactions. The boxes indicate the nicotinamide (NAM) and adenosine diphosphate-ribose (ADPR) moieties that are released after cleavage by NAD+-consuming enzymes. B. NAD+ and its vitamin B3 precursors NAM and nicotinamide riboside (NR) can be found in the extracellular compartment. NAD+ synthetic pathways are highlighted in green and consuming pathways are highlighted in red. NAD+ present in food is broken down into nicotinamide mononucleotide (NMN), NAM or NR components. NMN is converted to NR by CD73 5′-ectonucleotidase. NR can enter the cells through nucleoside transporters. The NAD+ biosynthetic pathways are initiated by the nicotinamide phosphoribosyl transferase (Nampt) and nicotinamide riboside kinase (Nmrk) enzymes forming NMN, followed by the nicotinamide mononucleotide adenylyl transferase (Nmnat) enzymes fusing an NMN to an ADP moiety to form NAD+. The NAD+ coenzyme is reduced to NADH during glycolysis, fatty acid β-oxidation (FAO) and mitochondrial oxidative phosphorylation, and is the precursor of oxidized/reduced NAD phosphate (NADP+/NADPH) in the cytosol and mitochondria. NAD+ is cleaved by enzymes, such as sirtuins (SIRT) and poly(ADPR) polymerases (PARP), involved in gene regulation for oxidative stress resistance and mitochondrial biogenesis. NAD is also used by ADP-ribosylases, such as ADP-ribosyl transferase C1 (ART1), located at the membrane. CD38 cleaves NAD+ to generate cyclic ADPR (cADPR) and ADPR second messengers or nicotinic acid adenine dinucleotide phosphate (NAADP) from NADP. The second messengers are involved in calcium (Ca2+) mobilization from the extracellular compartment (Trpm2) and intracellular stores, notably the sarcoplasmic reticulum, through the activation of the ryanodin receptor (RyR) or the lysosomal stores. Ac: acetyl; ATP: adenosine triphosphate; CoA: coenzyme A; ETC: electron transport chain; FoxO: forkhead box O; GSH: glutathione; Idh2: isocitrate dehydrogenase 2; NADK: NAD kinase; Nnt: nicotinamide nucleotide transhydrogenase; NOX: NADPH oxidase; Nrt1: nitrate transporter 1; PGC: peroxisome proliferator-activated receptor gamma coactivator; ROS: reactive oxygen species; Trpm2: transient receptor potential cation channel, subfamily M, member 2; TXN: thioredoxin.

Figure 2

Figure 2 : 

Therapeutic potential of compounds modulating oxidized nicotinamide adenine dinucleotide (NAD+) homeostasis and signalling in heart failure. Vitamin B3 (nicotinic acid [NA] and NA derivatives, such as acipimox, nicotinamide [NAM] and nicotinamide riboside [NR]) and nicotinamide mononucleotide (NMN) can be used to stimulate NAD+ synthesis and oxidative metabolism. NAM is not only a precursor of NAD+ but also an inhibitor of sirtuins, so its use maybe counterproductive. Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (e.g. olaparib, veliparib, niraparib, L-2286 and AG-690/11026014) can limit the high NAD+ consumption by PARP1 and have been shown to be beneficial in preclinical models. Alternatively, inhibitors of the other major NAD+ hydrolase CD38 (e.g. 4-amino-8-quinoline carboxamide compounds, daratumumab [HuMax®-CD38; Genmab, Copenhagen, Denmark] a human immunoglobulin G1κ monoclonal antibody) could help to maintain NAD concentrations in the myocardium, although they have not been tested in preclinical models of heart failure as yet. Sirtuins consume NAD+, but at moderate level and, overall, their action is thought to be protective in the context of pathological cardiac remodelling. This hypothesis is supported by the beneficial action of sirtuin activators on cardiovascular health (e.g. resveratrol, SRT1460, SRT1720, SRT2183, STAC-5, STAC-9, STAC-10). Importantly, a beneficial side effect of sirtuin-1 (SIRT1) activators could be repression of deleterious PARP1 activity. Ca2+: calcium.

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