Emerging potential benefits of modulating NAD+ metabolism in cardiovascular disease

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) and related metabolites are central mediators of fuel oxidation and bioenergetics within cardiomyocytes. Additionally, NAD⁺ is required for the activity of multifunctional enzymes, including sirtuins and poly(ADP-ribose) polymerases that regulate posttranslational modifications, DNA damage responses, and Ca²⁺ signaling. Recent research has indicated that NAD⁺ participates in a multitude of processes dysregulated in cardiovascular diseases. Therefore, supplementation of NAD⁺ precursors, including nicotinamide riboside that boosts or repletes the NAD⁺ metabolome, may be cardioprotective. This review examines the molecular physiology and preclinical data with respect to NAD⁺ precursors in heart failure-related cardiac remodeling, ischemic-reperfusion injury, and arrhythmias. In addition, alternative NAD⁺-boosting strategies and potential systemic effects of NAD⁺ supplementation with implications on cardiovascular health and disease are surveyed.

Keywords: cardiovascular diseases; ischemia-reperfusion; nicotinamide adenine dinucleotide; oxidation-reduction (redox).

Fig. 1.

Nicotinamide adenine dinucleotide (NAD⁺) in cardiac metabolism. NAD⁺ is used in fuel metabolism within the heart. The predominant substrate for energy production in the cardiomyocyte is fatty acids. Through fatty acid β-oxidation (FAO), NAD⁺ is reduced to NADH. NADH is used and oxidized to NAD⁺ in oxidative phosphorylation to produce ATP. Within conditions of mitochondrial dysfunction and ischemia, the heart relies on carbohydrates and glycolysis for the generation of ATP. Glycolysis reduces NAD⁺ to NADH. Subsequently, pyruvate is converted to lactate by lactate dehydrogenase to aid in the regeneration of the oxidized NAD⁺. Glucose 6-phosphate from the glycolytic pathway can be shunted to the pentose phosphate shuttle where the phosphorylated form of NAD⁺ (NADP⁺) is reduced to NADPH. Acetyl-CoA can be generated from pyruvate, ketone bodies, and amino acids to participate in the tricarboxylic acid (TCA) cycle. The generation of α-ketoglutarate (α-KG) from amino acids can also contribute in energy production within the TCA cycle. Metabolic reprogramming in failing hearts away from FAO and toward glycolytic and ketone body oxidation is predicted to decrease the NAD⁺-to-NADH ratio, having major implications in cellular processes. Furthermore, decreasing NAD⁺ content by downregulation of biosynthesis or upregulation of consumption may limit metabolic processes.

Fig. 2.

Biosynthesis and consumption of NAD⁺. NAD⁺ is produced from the following 4 precursors: tryptophan, nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide (NAM). Through the de novo pathway, tryptophan is converted to quinolate through the kynurenine pathway. Quinolate is converted to nicotinic acid mononucleotide (NAMN) by quinolate phosphoribosyltransferase (QPRT). In addition, nicotinic acid is converted to NAMN by nicotinic acid phosphotransferase (NAPRT1). NAMN is converted to nicotinic acid adenine dinucleotide (NAAD) by nicotinamide mononucleotide adenylate transferase. Nicotinamide riboside and nicotinamide are converted to nicotinamide mononucleotide (NMN) by nicotinamide riboside kinases (NMRKs) and nicotinamide phosphotransferase (NAMPT), respectively. In addition, NR can be degraded to NAM by purine nucleoside phosphorylase (PNP). NMN is converted to NAD⁺ by NMN adenlyltransferase (NMNAT). NAD⁺ can be consumed by the following 3 classes of enzymes: sirtuins, poly(ADP-ribose) polymerases, and cADP-ribose synthetases. A byproduct of consumption is NAM, which can be recycled back to produce NAD⁺.

Fig. 3.

Regulation of Na_v1.5 membrane expression by NAD⁺ and NADH. The III−IV intracellular domain of Na_v1.5, historically known for its involvement in channel gating, has more recently been identified as a critical site for posttranslational modifications (PTMs) that regulate channel surface expression. Glycerol-3-phosphate dehydrogenase 1-like (GPD1L) interacts with Na_v1.5 and modulates these PTMs. GPD1L interconverts glycerol 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) using NAD⁺ and NADH as coenzymes. NAD⁺ increases channel membrane expression by activating PKA phosphorylation on the I-II intracellular linking domain in addition to boosting sirtuin (SIRT)1 deacetylation of lysine residue K1479 within the III−IV intracellular linking domain. NADH has been shown to decrease channel membrane expression and single channel conductance by activating PKC, which phosphorylates S1503 within the III−IV linking domain. PKC is also activated by a downstream metabolite of G3P, diacylglycerol (DAG). In a catalytically inactive mutant of GPD1L, a known A280V mutation among others predispose individuals to fatal arrhythmias and Brugada Syndrome, this regulation is disturbed.

Fig. 4.

NAD⁺ and Ca²⁺ signaling in arrhythmogenesis. NAD⁺ can be converted to cADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) by cADPR synthetases, including CD38, which can serve as both a cyclase and hydrolase for the subsequent conversion of cADPR to acylated ADP-ribose (ADPR). cADPR and NAADP trigger a cascade of events, including the activation of the Na⁺/Ca²⁺ exchanger (NCX), that may lead to the propagation of ventricular arrhythmias. NADH-dependent reactive oxygen species (ROS) accumulation by an unidentified cytoplasmic flavoprotein oxidase has been shown to inhibit NCX. Collectively, redox regulation and NAD⁺ metabolism hold the ability to regulate Ca²⁺ handling and electrical activity in the heart.

Fig. 5.

Effects of boosting NAD⁺ in the heart. NAD⁺ precursor vitamins boost the cardiac NAD⁺ metabolome, resulting in 1) increased sirtuin activity, 2) increased NAD⁺/NADH redox balance, and 3) elevated NADPH. Pharmacological NAM is a sirtuin (SIRT) inhibitor, and its conversion to NMN through NAMPT is downregulated in pathological cardiac stress, including models of ischemia/reperfusion (I/R) injury and pressure overload hypertrophy. However, NMRK2 has been shown to be upregulated in the presence of cardiac stress, including a mouse model of dilated cardiomyopathy, suggesting that NR is the preferred agent for cardioprotection. Although SIRT1, SIRT2, SIRT3, and SIRT6 are generally regarded as cardioprotective, the mitochondrial SIRT4 appears to induce cardiac stress and damage.