Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
Acta Physiol (Oxf). 2021 Mar;231(3):e13551. doi: 10.1111/apha.13551. Epub 2020 Sep 21.
Nicotinamide adenine dinucleotide (NAD) is an abundant cofactor that plays crucial roles in several cellular processes. NAD can be synthesized de novo starting with tryptophan, or from salvage pathways starting with NAD precursors like nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR), referred to as niacin/B vitamins, arising from dietary supply or from cellular NAD catabolism. Given the interconversion between its oxidized (NAD ) and reduced form (NADH), NAD participates in a wide range of reactions: regulation of cellular redox status, energy metabolism and mitochondrial biogenesis. Plus, NAD acts as a signalling molecule, being a cosubstrate for several enzymes such as sirtuins, poly-ADP-ribose-polymerases (PARPs) and some ectoenzymes like CD38, regulating critical biological processes like gene expression, DNA repair, calcium signalling and circadian rhythms. Given the large number of mitochondria present in cardiac tissue, the heart has the highest NAD levels and is one of the most metabolically demanding organs. In several models of heart failure, myocardial NAD levels are depressed and this depression is caused by mitochondrial dysfunction, metabolic remodelling and inflammation. Emerging evidence suggests that regulating NAD homeostasis by NAD precursor supplementation has therapeutic efficiency in improving myocardial bioenergetics and function. This review provides an overview of the latest understanding of the different NAD biosynthesis pathways, as well as its role as a signalling molecule particularly in cardiac tissue. We highlight the significance of preserving NAD equilibrium in various models of heart diseases and shed light on the potential pharmacological interventions aiming to use NAD boosters as therapeutic agents.
烟酰胺腺嘌呤二核苷酸 (NAD) 是一种丰富的辅因子，在许多细胞过程中发挥着关键作用。NAD 可以从头合成色氨酸开始，也可以从 NAD 前体如烟酸 (NA)、烟酰胺 (NAM) 或烟酰胺核苷 (NR) 的补救途径开始，这些前体被称为烟酸/B 族维生素，来自饮食供应或细胞 NAD 分解代谢。由于其氧化 (NAD+) 和还原形式 (NADH) 之间的相互转换，NAD 参与了广泛的反应：调节细胞氧化还原状态、能量代谢和线粒体生物发生。此外，NAD 作为一种信号分子，是几种酶的辅助底物，如沉默调节蛋白、多聚 ADP-核糖聚合酶 (PARPs) 和一些细胞外酶，如 CD38，调节关键的生物过程，如基因表达、DNA 修复、钙信号和昼夜节律。鉴于心脏组织中存在大量的线粒体，心脏具有最高的 NAD 水平，是代谢需求最高的器官之一。在心力衰竭的几种模型中，心肌 NAD 水平降低，这种降低是由线粒体功能障碍、代谢重塑和炎症引起的。新出现的证据表明，通过 NAD 前体补充来调节 NAD 动态平衡在改善心肌生物能量和功能方面具有治疗效果。本综述提供了对不同 NAD 生物合成途径的最新理解的概述，以及 NAD 作为信号分子特别是在心脏组织中的作用。我们强调了在各种心脏疾病模型中保持 NAD 平衡的重要性，并探讨了旨在将 NAD 增强剂用作治疗剂的潜在药理学干预措施。
