NAD+ metabolism and therapeutic strategies in cardiovascular diseases

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a central and pleiotropic metabolite involved in cellular energy metabolism, cell signaling, DNA repair, and protein modifications. Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Metabolic stress and aging directly affect the cardiovascular system. Compelling data suggest that NAD + levels decrease with age, obesity, and hypertension, which are all notable risk factors for CVD. In addition, the therapeutic elevation of NAD + levels reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular disorders. In preclinical models, NAD + boosting can also expand the health span, prevent metabolic syndrome, and decrease blood pressure. Moreover, NAD + storage by genetic, pharmacological, or natural dietary NAD + -increasing strategies has recently been shown to be effective in improving the pathophysiology of cardiac and vascular health in different animal models, and human health. Here, we review and discuss NAD + -related mechanisms pivotal for vascular health and summarize recent experimental evidence in NAD + research directly related to vascular disease, including atherosclerosis, and coronary artery disease. Finally, we comparatively assess distinct NAD + precursors for their clinical efficacy and the efficiency of NAD + elevation in the treatment of major CVD. These findings may provide ideas for new therapeutic strategies to prevent and treat CVD in the clinic.

Keywords: Atherosclerosis; Cardiovascular diseases; Nicotinamide adenine dinucleotide; Vascular disorder.

Graphical abstract

Fig. 1

NAD + metabolism in mammals. NAD + homeostasis is maintained by synthesis, consumption and regeneration in different pathways regulated by specific NAD + -consuming enzymes, generation enzymes and redox reactions. A: NAD + biosynthetic pathway. Three independent pathways maintain NAD + levels. The dietary amino acid Trp is converted to NAD + via a de novo synthesis pathway. After Trp enters the cytoplasm, the rate-limiting enzyme (IDO/TDO) will transfer Trp to FK. Following several steps, the ACMS was generated and condensed into Qa spontaneously; subsequently, Qa was converted to QPRT to produce NAMN, which converges with the Preiss-Handler pathway. The Press-Handler pathway uses NA as the original material. NA can be converted to NAMN via the NAPRT enzyme, followed by NAAD generation via NMNAT enzymes; in the end, NAD+ is generated via NADS synthetase. The salvage pathway mainly involves recycling the byproduct NAM generated during NAD + consumption. In the cytoplasm, NAMPT converts NAM to NMN, one of the NAD + precursors, and NMNATs will convert NMN into NAD+. In the extracellular space, NAM is transformed into NMN first, and NMN is then dephosphorylated by CD73 to NR. NR is converted to NMN via NRK enzymes in the intracellular space. Ultimately, NAD+ is generated via NMNATs. B: NAD + consumption. NAD + acts as a cosubstrate for a wide variety of enzymes, including PARPs, sirtuins, CD38/CD157, and SARM1. These enzymes use NAD + as a cosubstrate to modulate various biological processes, generating their byproduct, i.e. NAM. These enzymes have an impact on DNA repair, RNA processing, metabolism, genomic stability, inflammation, cell adhesion, and stress resistance. Abbreviations: NAD+, nicotinamide adenine dinucleotide; IDOs, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; QA, quinolinic acid; NAMN, nicotinate mononucleotide; QPRT, quinolinate phosphoribosyl-transferase; NAPRT, nicotinic acid phosphoribosyltransferase; NMNATs, nicotinamide mononucleotide adenylyl transferases; NR, nicotinamide riboside; Trp, tryptophan; PARPs, poly (ADP-ribose) polymerases; NNMT, nicotinamide N-methyltransferase; NMN, nicotinamide mononucleotide; NAM, nicotinamide; NA, nicotinic acid. NAMPT, Nicotinamide phosphoribosyltransferase.

Fig. 2

NAD + in vascular health and function. NAD + has multiple roles in maintaining vascular health. On the one hand, decreased NAD + levels reduce mitochondrial function and autophagy, leading to increased numbers of damaged mitochondria, apoptotic cells and damaged DNA. On the other hand, suppressed NAD + levels also enhance the inflammatory response, oxidative stress and protein acetylation, which lower blood flow and restrain endothelial mobility and lipid homeostasis. Together, this furthers the prevalence of CVD. Abbreviations: NAD+, nicotinamide adenine dinucleotide; CVD, cardiovascular disease.

Fig. 3

Therapeutic approaches to restore NAD + levels and their impact on CVD. Several strategies can boost NAD + levels, including supplementation with NAD + precursors, inhibition of NAD + -consuming enzymes via pharmacy, fasting or taking a healthy diet, and increased exercise and NAD + -boosting strategies can develop better CVD outcomes. In Atherosclerosis, high NAD + levels can reduce chronic inflammation and decrease LDL-cholesterol levels. It can also increase endothelial function and vasodilation. In coronary disease, elevation of NAD + levels can increase autophagy and mitochondrial function and lessen ROS release, inflammation, and tissue necrosis. Abbreviations: NAD+, nicotinamide adenine dinucleotide; CVD, cardiovascular disease; HDL, high-density lipoprotein, LDL, low-density lipoprotein; NO, nitric oxide; ROS, reactive oxygen species.