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. 2025 May:404:119188.
doi: 10.1016/j.atherosclerosis.2025.119188. Epub 2025 Apr 3.

NAD+ boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice

Yu-Jen Wang  1 , Daniel S Gaul  2 , Era Gorica  1 , Jürgen Pahla  2 , Zeneng Wang  3 , Shafeeq A Mohammed  1 , Tina Dahlby  4 , Elisa Dietrich  5 , Elena Osto  6 , Karim Gariani  7 , Sarah Costantino  1 , Stephan Winnik  8 , Sokrates Stein  1 , Stanley L Hazen  9 , Frank Ruschitzka  1 , Johan Auwerx  10 , Christian M Matter  11
Affiliations
Free article

NAD+ boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice

Yu-Jen Wang et al. Atherosclerosis. 2025 May.
Free article

Abstract

Background and aims: 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 (N1-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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Atherosclerosis; CD38; Liver; Macrophage; Nicotinamide adenine dinucleotide (NAD(+)); Nicotinamide riboside (NR).

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CMM has received research grants to the institution from EliLilly, AstraZeneca, Roche, Amgen, Novartis, Novo Nordisk and MSD including speaker or consultant fees. FR has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in Switzerland, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research-, educational- and/or travel grants from Abbott, Abiomed, Alnylam, Amarin, Amgen, Astra Zeneca, At the Limits Ltd., Bayer, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, CM Microport, Concept Medical, CTI, Daiichi Sankyo, Edwards Lifesciences, FomF GmbH, Hamilton Health Sciences, IHF, Innosuisse, IumiraDX, Kantar, LabPoint, MedAlliance, Medcon International, Medical Education Global Solutions, Medtronic, MicroPort, Monocle, Novartis, Novo Nordisk, OM Pharma, Pfizer, Quintiles Switzerland Sarl, RecorMedical, Roche Diagnostics, Roche Pharma, Sahajanand IN, Sanofi, Sarstedt AG, Servier, Terumo Deutschland, Trama Solutions, V- Wave, Vifor, ZOLL. These grants do not impact his personal remuneration. SLH and ZW report being named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a wholly owned subsidiary of Quest Diagnostics, Procter & Gamble and Zehna Therapeutics. SLH reports being a paid consultant for Zehna Therapeutics and having received research funds from Zehna Therapeutics. SW reports educational grant support through his institution and/or travel support and/or consulting/speaker fees from Abbott, Bayer, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston-Scientific, Cardinal Health, Daichi-Sankyo, Fehling Instruments, Medtronic, Servier, and Zoll.

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