Wang Yu-Jen, Gaul Daniel S, Gorica Era, Pahla Jürgen, Wang Zeneng, Mohammed Shafeeq A, Dahlby Tina, Dietrich Elisa, Osto Elena, Gariani Karim, Costantino Sarah, Winnik Stephan, Stein Sokrates, Hazen Stanley L, Ruschitzka Frank, Auwerx Johan, Matter Christian M
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Zurich, Switzerland.
Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
Atherosclerosis. 2025 May;404:119188. doi: 10.1016/j.atherosclerosis.2025.119188. Epub 2025 Apr 3.
NAD (nicotinamide adenine dinucleotide) is a cosubstrate of the sirtuins (SIRT) that are activated upon caloric restriction. Supplementing NAD precursors such as nicotinamide riboside (NR) has been reported to extend life span and combat metabolic syndrome through pan-sirtuin activation in mice. Notably, sirtuins compete with poly (ADP-ribose) polymerase (PARP)1 and CD38 for NAD. Supplementing NAD precursors did not improve cardiovascular outcome in the AIM-HIGH trial. Recently, the terminal NAD metabolite 4PY (N-methyl-4-pyridone-3-carboxamide) was reported to increase inflammation and to be associated with cardiovascular risk. We aimed to investigate whether NR provides atheroprotection.
8-week-old male apolipoprotein E (Apoe) knockout mice were fed for 12 weeks a high-cholesterol diet supplemented with three NR doses: NR-, NR+, and NR++. RAW264.7 mouse macrophages and bone marrow macrophages were stimulated with oxLDL and NR.
NR++ enhanced plaque lesions in aortic sinus sections and increased plasma levels of TNFα, IL-6, and LDL-cholesterol. Liver and plasma NAD concentrations remained unchanged, but the downstream metabolite 4PY increased. In liver lysates, SIRT1 and lipoprotein receptors were decreased and CD38 increased in NR++; cleaved PARP1 and total PARylation decreased upon NR supplementation. In oxLDL-treated macrophages, high NR levels increased CD38 and CD86 expression.
High-dose NR supplementation in mice did not decrease but increase both aortic plaque lesions and systemic inflammation. These effects may be mediated by increased CD38 expression in macrophages, with NAD metabolism shifted from sirtuins towards CD38 and PARP1 pathways. Caution should be applied with presumed NAD boosters in patients with atherosclerosis.
烟酰胺腺嘌呤二核苷酸（NAD）是在热量限制时被激活的去乙酰化酶（SIRT）的共底物。据报道，补充NAD前体如烟酰胺核糖（NR）可通过激活小鼠体内的泛去乙酰化酶来延长寿命并对抗代谢综合征。值得注意的是，去乙酰化酶与聚（ADP - 核糖）聚合酶（PARP）1和CD38竞争NAD。在AIM - HIGH试验中，补充NAD前体并未改善心血管结局。最近，据报道NAD的终末代谢产物4 - PY（N - 甲基 - 4 - 吡啶酮 - 3 - 甲酰胺）会增加炎症并与心血管风险相关。我们旨在研究NR是否具有抗动脉粥样硬化保护作用。
给8周龄雄性载脂蛋白E（Apoe）基因敲除小鼠喂食高胆固醇饮食12周，饮食中添加三种剂量的NR：NR - 、NR + 和NR ++ 。用氧化低密度脂蛋白（oxLDL）和NR刺激RAW264.7小鼠巨噬细胞和骨髓巨噬细胞。
NR ++ 组增强了主动脉窦切片中的斑块病变，并增加了血浆中肿瘤坏死因子α（TNFα）、白细胞介素 - 6（IL - 6）和低密度脂蛋白胆固醇（LDL - 胆固醇）的水平。肝脏和血浆中的NAD浓度保持不变，但下游代谢产物4 - PY增加。在肝脏裂解物中，NR ++ 组中SIRT1和脂蛋白受体减少，CD38增加；补充NR后，裂解的PARP1和总PAR化水平降低。在用oxLDL处理的巨噬细胞中，高浓度NR增加了CD38和CD86的表达。
在小鼠中补充高剂量NR并未减少反而增加了主动脉斑块病变和全身炎症。这些作用可能是由巨噬细胞中CD38表达增加介导的，NAD代谢从去乙酰化酶途径转向CDA38和PARP1途径。对于动脉粥样硬化患者，应谨慎使用假定的NAD增强剂。
