Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rathner, T.
Role of NAD+ levels in Western Diet-induced atherosclerosis
Humanmedizin; [ Diplomarbeit ] Medizinische Universität Graz; 2024. pp. 73
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Bugger Heiko Matthias
- Byrne Nikole
- Altmetrics:
- Abstract:
- Background: Atherosclerosis is an inflammatory disease and a main contributor to cardiovascular death. The coenzyme nicotinamide adenine dinucleotide (NAD+) is of central importance in metabolism, as it transports hydrogen and electrons to the electron transport chain and acts as a co-substrate for several metabolic enzymes. It has been shown that NAD+ depletion induces a pro-inflammatory response and is associated with the progression of atherosclerosis. NAD+ precursors, such as nicotinamide mononucleotide (NMN), have been shown to replenish NAD+ levels in several tissues. The aim of this study was to demonstrate the effect of NMN-treatment on the development of atherosclerosis. Methods: 8-week-old C57BL/6J male low density lipoprotein receptor knockout (Ldlr-/-) mice were fed a chow diet or a western diet (WD) containing 1.25 % cholesterol. After 8 weeks of diet, half the mice from each diet were supplemented with NMN in the drinking water (500 mg/kg/day) (n=6 per group). We performed glucose tolerance tests, plasma lipid measurements, leukocyte isolation from bone marrow and spleen, NAD+ quantification, automated western blotting, RT-qPCR and Oil Red O staining of the aortic root and arch. Results: Oil red O staining showed distinct atherosclerotic lesions in the WD-fed group. NMN-treatment significantly reduced atherosclerosis of WD-fed mice. NAD+ levels were significantly decreased in spleen leukocytes of WD-fed mice, accompanied by increased expression of NAD+-producing (Nampt, Nmnat1) and NAD+-consuming (Parp1, Cd38, Sirt3) enzymes. NMN treatment restored NAD+ levels and blunted the alterations in gene expression. Acetylation of manganese superoxide dismutase (MnSOD), a target of the NAD+-dependent deacetylase SIRT3, was increased in WD-fed mice, indicating reduced SIRT3 activity following WD feeding. WD also increased leukocyte expression of the SIRT3-regulated inflammasome component, NLRP3, an effect that was blunted in response to NMN treatment. Conclusion: NMN treatment attenuated the development of atherosclerosis, indicating that NAD+ depletion contributes to atherosclerosis pathogenesis, possibly by impairing SIRT3 activity and amplifying NLRP3 activity in leukocytes. Thus, NAD+ supplementation may be a promising strategy to attenuate or prevent development of atherosclerosis.