Year: 2025
Type: 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.
Authors: Wang, Yu-Jen, Gaul, Daniel S., Gorica, Era, Pahla, Jürgen, Wang, Zeneng, Mohammed, Shafeeq, Dahlby, Tina, Dietrich, Elisa, Osto, Elena, Gariani, Karim, Costantino, Sarah, Winnik, Stephan, Stein, Sokrates, Hazen, Stanley L., Ruschitzka, Frank, Auwerx, Johan, Matter, Christian M.
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6966375100
FWCI:
Cites:
Cited by:
Related to: