Nicotinamide Riboside for the Prevention and Treatment of Doxorubicin Cardiomyopathy. Opportunities and Prospects

Figures

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  Figure 1. Features of the development of doxorubicin cardiomypathy.

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  Figure 2. NAD+ biosynthetic pathways. De novo biosynthesis begins with the conversion of tryptophan (Trp) to N-L-formylkynurenine either by indolamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO). After four reaction steps, N-L-formylkynurenine can subsequently be converted to the unstable 2-amino-3-carboxymuconate-6-semialdehyde acid, which can undergo nonenzymatic cyclization to quinolinic acid. The last step of de novo biosynthesis consists of the quinolinate-catalyzed phosphoribosyltransferase (QPRT) formation of NA mononucleotide (NaMN) using PRPP (5-phosphoribosyl 1-pyrophosphate). The Preiss-Handler pathway is initiated by NA phosphoribosyltransferase (NAPRT) to form NaMN. Further, NAMN is converted into adenine dinucleotide NA (NAAD) by the enzymes NMN adenylyltransferase (NMNAT1-3) together with ATP. Finally, NAAD is converted to NAD+ via an amidation reaction catalyzed by the enzyme NAD+ synthase (NADSYN). The Core Recycling and Salvage Pathways are the shortest ways to synthesize NAD+ from NAM and NR (2 steps). NAM is converted by the rate-limiting nicotinamide phosphoribosyltransferase (NAMPT) to form NMN using PRPP as a cosubstrate. NMN is also a product of NR…

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  Figure 3. The balance of NAD+ is the balance of synthesis, consumption and recirculation in various subcellular compartments (cytoplasm, nucleus and mitochondria). After entering the cell, NAD+ precursors are metabolized by four main pathways (Figure 1) to NAD+. In the cytosol, nicotinamide (NAM) is converted to nicotinamide mononucleotide (NMN) by the intracellular form of NAM phosphoribosyltransferase (iNAMPT). NMN is then converted to NAD+ by NMN transferase 2 (NMNAT2) bound to the outer Golgi membrane in the cytoplasm. NAD+ is converted to NADH/NADPH during the redox cycle, used during aerobic/anaerobic glycolysis and is consumed by NAD-dependent enzymes (SIRT2, PARP1-3, CD38/157, SARM1). In mitochondria, NMN is converted to NAD+ by NMNAT3. NAD+ is used by the TCA cycle to generate ATP and is additionally used by mitochondrial sirtuins 3–5 (SIRT3-5) and PARP1, which generate NAM. Studies show the presence of NAD+, NADH and NMN transporters in the mitochondrial membrane, but no specific transporters have yet been identified [27]. It is still not clear whether NAM can be converted back to NMN within the mitochondria, or whether it is transported/diffused from the mitochondria into the…

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  Figure 4. Hypothesis of the impact of NR in the development of doxorubicin cardiomyopathy. It is a popular assumption that the development of doxorubicin (DOX) cardiotoxicity occurs due to the massive generation of ROS, which in turn is caused by a secondary mechanism due to the suppression of topoisomerase 2β. In consequence DNA damage increases, enzymes involved in its repair, PARPs and CD38, are activated, while the activity of sirtuins and NAMPT (the main pathway of NAD+ synthesis through NAM under normal physiological conditions, Core Recycling Pathway) is suppressed, and the work of Complex I in the electron transport chain is disrupted, using NADH as an electron donor creating NAD+. Damage to Complex 1 and ATP production leads to accumulation of ROS that increase oxidative stress. Separately doxorubicin reduces tight junction formation by decreasing the expression of the occluded zone (ZO)−1, which can increase doxorubicin levels in the capillary endothelium of the heart muscle. This also reduces nitric oxide (NO) level by enzymatic inhibition, reducing the level of endothelin (ET)−1 accumulation of ROS [116]. All mechanisms lead to a significant decrease in NAD+ levels, the…