1Medical University of Graz Kardiologie Graz, Österreich
Depletion of tissue NAD+ levels is frequently observed in the metabolic syndrome. Therapeutic effects of NAD+ repletion on cardiovascular disease remain incompletely investigated. Here we fed Ldlr-/- mice chow or western diet (WD) for a total of 16 weeks and administered either the NAD+ precursor, nicotinamide mononucleotide (NMN), or vehicle starting at week 9 of WD feeding. Increased body weight, elevated free fatty acid, cholesterol and glucose levels, and impaired glucose tolerance in WD mice were unaffected by NMN supplementation. However, NMN treatment attenuated plaque growth in the aortic root of WD-fed mice. Based on the fact that inflammation contributes to onset and progression of atherosclerosis, and NAD+ metabolism determines inflammatory activity of immune cells, we determined NAD+ levels and expression of NAD+ metabolic enzymes in leukocytes derived from bone marrow (BM) and spleen of chow- and WD-fed mice following vehicle or NMN treatment. Interestingly, NAD+ levels were significantly reduced in BM-derived leukocytes and expression of key NAD+-producing (Nampt, Nmnat) and consuming (Parp1, Cd38, Sirt3) enzymes were significantly upregulated in spleen-derived leukocytes following WD feeding. Moreover, acetylation of the SIRT3 target, mitochondrial superoxide dismutase (MnSOD), and expression of markers of the NLRP3 inflammasome (Nlrp3, Il1b, Tnfa) were significantly increased in spleen-derived leukocytes from WD-fed mice. Following NMN treatment, SIRT3 protein expression tended to increase (p=0.07) and upregulated expression of NAD+ metabolic enzymes and Nlrp3 were blunted. Thus, NMN supplementation attenuated plaque progression in a model of cardiometabolic disease and atherosclerosis, potentially involving modulation of leukocyte NAD+ metabolism and activition of SIRT3.