title: Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid.
abstract: 1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/LDLR(-/-) mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F1 α and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR(-/-) mice, an effect associated with an improvement in prostacyclin- and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA.
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Lukasz
authors.initials: L
authors.lastname: Mateuszuk
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jasztal
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Edyta
authors.initials: E
authors.lastname: Maslak
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Marlena
authors.initials: M
authors.lastname: Gasior-Glogowska
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Baranska
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Renata
authors.initials: R
authors.lastname: Kostogrys
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zakrzewska
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kij
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.).
authors.forename: Maria
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (Ł.M., A.J., E.M., M.G.-G., M.B., B.S., A.Z., A.K., M.W., S.C.) and Faculty of Chemistry (M.B.), Jagiellonian University, Krakow, Poland; Department of Toxicology, Faculty of Pharmacy (A.K., M.W.) and Chair of Pharmacology (S.C.), Jagiellonian University Medical College, Krakow, Poland; and Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland (R.K.) stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009525:Niacin / Q000494:pharmacology / Q000627:therapeutic use*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D011973:Receptors, LDL / Q000172:deficiency*; D016896:Treatment Outcome
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; D009536:Niacinamide; D009525:Niacin; C024058:N(1)-methylnicotinamide