Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
Nat Cardiovasc Res. 2024 Oct;3(10):1236-1248. doi: 10.1038/s44161-024-00542-9. Epub 2024 Sep 18.
Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD levels, and supplementation with NAD precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD loss as all were ameliorated by restoring cardiac NAD levels with the NAD precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.
烟酰胺腺嘌呤二核苷酸 (NAD) 是代谢反应中的必需辅酶，也是信号酶的辅助底物。心力衰竭患者的主要 NAD 生物合成酶烟酰胺磷酸核糖基转移酶 (Nampt) 表达降低，NAD 水平降低，而 NAD 前体的补充在临床前模型中具有保护作用。在这里，我们表明，成年心肌细胞中的 Nampt 缺失导致 NAD 耗竭，同时伴有明显的代谢紊乱、肥大重塑和心脏性猝死，尽管射血分数、耐力和线粒体呼吸能力没有变化。这些影响可以直接归因于 NAD 的缺失，因为用 NAD 前体烟酰胺核糖苷 (NR) 恢复心脏 NAD 水平可以改善所有这些影响。心电图显示，心肌 Nampt 的缺失导致 QT 间期缩短，并伴有自发性致命性心律失常导致心脏性猝死。因此，即使在足以维持能量的水平，NAD 浓度的变化也会对心脏生理学产生深远的影响。
