Harnessing NAD+ Metabolism as Therapy for Cardiometabolic Diseases

Abstract

Purpose of the review: This review summarizes current understanding on the roles of nicotinamide adenine dinucleotide (NAD⁺) metabolism in the pathogeneses and treatment development of metabolic and cardiac diseases.

Recent findings: NAD⁺ was identified as a redox cofactor in metabolism and a co-substrate for a wide range of NAD⁺-dependent enzymes. NAD⁺ redox imbalance and depletion are associated with many pathologies where metabolism plays a key role, for example cardiometabolic diseases. This review is to delineate the current knowledge about harnessing NAD⁺ metabolism as potential therapy for cardiometabolic diseases. The review has summarized how NAD⁺ redox imbalance and depletion contribute to the pathogeneses of cardiometabolic diseases. Therapeutic evidence involving activation of NAD⁺ synthesis in pre-clinical and clinical studies was discussed. While activation of NAD⁺ synthesis shows great promise for therapy, the field of NAD⁺ metabolism is rapidly evolving. Therefore, it is expected that new mechanisms will be discovered as therapeutic targets for cardiometabolic diseases.

Keywords: Cardiometabolic diseases; Heart failure; NAD+ metabolism; Redox balance.

Figure 1:. NAD⁺ redox balance, consumption and synthesis.

Redox turnover of NAD⁺ is essential for substrate catabolism, e.g. glycolysis (green). NAD⁺ is consumed as a substrate by Sirtuins, Parps and NAD⁺ hydrolases, yielding NAM and an ADPR moiety. These NAD⁺-consuming enzymes regulate PTMs of proteins, NAD⁺ levels and cellular functions. NAD⁺ is synthesized through three pathways- the de novo pathway (blue), the Preiss-Handler Pathway (yellow) and the salvage pathway (orange). De novo NAD⁺ synthesis starts with IDO, mediating the rate-limiting step with the conversion of tryptophan to N-formylkin. After several enzymatic reactions, the intermediate, ACMS, undergoes spontaneous cyclization to form QA, which is the second rate-limiting step. ACMS can be further metabolized to AMS by ACMSD and enter TCA cycle. Inhibition of ACMSD is reported to elevate NAD⁺ levels by directing ACMS to NAD⁺ synthesis via QA. QA is converted to NAMN by QPRT using PRPP as a co-substrate. In the Preiss-Handler pathway, NA is metabolized to NAMN by NAPRT. The de novo and Preiss–Handler pathways converge at NAMN, which is further metabolized into NAAD by NMNATs at the expense of ATP. NAD⁺ is synthesized from NAAD under the catalysis of NADS. NAM from NAD⁺ consumption and NR from diet serve as NAD⁺ precursors for the salvage pathway, in which NAM and NR are converted into a common product, NMN, by NAMPT or NMRK, respectively. NMN is converted into NAD⁺ by NMNAT, the same enzymes used in the Preiss-Handler pathways. Abbreviations: poly-ADP-ribose polymerases (Parps), nicotinamide phosphoribosyltransferase (Nampt), nicotinamide mononucleotide adenylyl transferases (Nmnats), NA phosphoribosyltransferase (Naprt), nicotinamide riboside kinases (Nmrks), quinolinic acid phosphoribosyltransferase (Qprt), indoleamine 2,3-dioxygenase (Ido), tryptophan 2,3-dioxygenase (Tdo), kynurenine monooxygenase (Kmo), kynureninase (Kynu), 3-hydroxyanthranilate-3,4-dioxygenase (Haao), ACMS decarboxylase (Acmsd), tryptophan (TRP), N-formylkynurenine (N-formylkin), L-kinurenine (L-KIN), 3-hydroxyanthranilate (3-HAA), α-amino-β-carboxymuconate-semialdehyde (ACMS), α-aminomuconate-semialdehyde (AMS), adenosine diphosphate ribose (ADPR), quinolinic acid (QA), nicotinic acid (NA), nicotinic acid mononucleotides (NAMN), nicotinic acid adenine dinucleotide (NAAD), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), post-translational modifications (PTMs).

Figure 2:. Impacts of cardiometabolic diseases and pharmacologic interventions on NAD⁺ homeostasis.

Cardiometabolic diseases are associated with NAD⁺ depletion. These stresses differentially impact NAD⁺ salvage pathway, which is the dominant synthesis pathway in the hearts. Failing hearts and diabetes promote NAD⁺ redox imbalance (low NAD⁺/NADH ratio), while failing hearts are also associated with lowered NAMPT expression. Failing hearts have up-regulated Nmrk2 expression, whose role in the pathogenesis is obscure. Pharmacologic agents to enhance NAD⁺ synthesis or to inhibit consumption increase cellular NAD⁺ levels. Boosting NAD⁺ levels via precursors such as NR and NMN, or NAMPT activation improves cardiac outcomes. Alternatively, inhibitions of PARPs (by INO1001, ABT-888) and CD38 (by 78c) demonstrate therapeutic effects.