Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Abstract

The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: −44%; NAM HD: −57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation.

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases

“…Both the resistance to oxidation of non-HDL and the antioxidant properties of HDL are two of the most important antiatherogenic metrics of lipoproteins ex vivo [ 83 ]. We recently reported that isolated plasma non-HDL from mice lacking apolipoprotein (Apo)E ( Apoe −/− ) treated with NAM was less susceptible to oxidation ex vivo than that from untreated mice [ 25 ]. Notably, incubation of human low-density lipoprotein (LDL) with NAM produced a direct inhibitory effect on lipid peroxidation during an analysis of the oxidation kinetics of exposed lipoproteins [ 25 ].…”

“…We recently reported that isolated plasma non-HDL from mice lacking apolipoprotein (Apo)E ( Apoe −/− ) treated with NAM was less susceptible to oxidation ex vivo than that from untreated mice [ 25 ]. Notably, incubation of human low-density lipoprotein (LDL) with NAM produced a direct inhibitory effect on lipid peroxidation during an analysis of the oxidation kinetics of exposed lipoproteins [ 25 ]. However, the effect of NAM on the HDL antioxidant capacity of Apoe −/− mice could not be evaluated in the latter study due to the limited circulating HDL moieties in this mouse model.…”

“…Treatment with both NAM and NA improved aneurysms in an experimental mouse model through GPR109A receptor-independent activity against this disease [ 24 ]. Unlike NA, NAM does not show strong lipid-lowering effects [ 19 ] but exerts antioxidant and anti-inflammatory effects [ 15 , 25 ]. Interestingly, NAM administration protected against beta pancreatic cell damage and loss and, thus, delayed the onset of diabetes mellitus type 1 in experimental models [ 26 ].…”

“…Although this effect was not reproduced in the ENDIT clinical trial [ 27 ], NAM administration at a dose of 1.2 g/m 2 did not cause adverse effects (including flushing) similar to those attributed to NA. Recent data from our own group show that NAM prevents inflammation and atherosclerosis in experimental animals [ 25 ]. Similarly, some other related compounds, such as NR [ 28 ], NMN [ 9 ], and N-methylated NAM (me-NAM) [ 29 , 30 ], seem to protect against vascular damage.…”

Thermodynamics and Intermolecular Interactions of Nicotinamide in Neat and Binary Solutions: Experimental Measurements and COSMO-RS Concentration Dependent Reactions Investigations

“…The beneficial effects associated with the use of nicotinamide have been found, not only in diseases directly related to vitamin B3 deficiency (e.g., pellagra), but also in other diseases such as hyperlipidemia [ 1 , 2 , 3 ], hypercholesterolemia [ 4 , 5 ], and even depression and other mental illnesses [ 6 , 7 , 8 ]. Nicotinamide has also been found to exhibit antioxidant properties [ 9 , 10 , 11 , 12 ]. Due to its solubilizing properties and beneficial properties for health, nicotinamide is a popular pharmaceutical excipient used in cocrystals and co-amorphous compositions, exhibiting improved active ingredient dissolution behavior [ 13 , 14 , 15 , 16 ].…”