Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor–Deficient Mice: A Comparison with Nicotinic Acid

Background: 1-methylnicotinamide (MNA) is a major endogenous metabolite of nicotinic acid (NicA). MNA displays anti-thrombotic and anti-inflammatory activity, both of which could partially contribute to the vasoprotective properties of NicA. In the present study we compare the anti-atherosclerotic effects of MNA and NicA in ApoE/LDLR-/- mice. Experimental approach: four-month-old ApoE/LDLR-/- mice were treated with an equimolar dose of MNA or NicA (100 mg kg-1). Plaque size and macrophages content in atherosclerotic plaques of the brachiocephalic artery (BCA), endothelial function (6-keto-PGF1α , nitrite/nitrate) in aortic rings, systemic inflammation, platelet activation, 2,3-dinor-6-keto-PGF1α and 2,3-dinor-TXB2 in urine as well as concentration of MNA metabolites were measured. Results: MNA and NicA reduced atherosclerotic plaque area and plaque inflammation in BCA. The anti-atherosclerotic actions of MNA and NicA were associated with improved endothelial function as evidenced by a higher concentration of 6-keto-PGF1α and nitrite/nitrate in the aortic effluent. NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and an 8-fold higher NA/MNA ratio in plasma, as compared with MNA treatment. Conclusions: MNA displays pronounced anti-atherosclerotic action in ApoE/LDLR-/- mice, an effect associated with an improvement in PGI2-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability following NicA treatment, as compared with an equimolar dose of MNA, the anti-atherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA may limit beneficial effects of NicA-derived MNA.