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Comparative Study
. 2016 Feb;356(2):514-24.
doi: 10.1124/jpet.115.228643. Epub 2015 Dec 2.

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

Lukasz Mateuszuk  1 , Agnieszka Jasztal  1 , Edyta Maslak  1 , Marlena Gasior-Glogowska  1 , Malgorzata Baranska  1 , Barbara Sitek  1 , Renata Kostogrys  1 , Agnieszka Zakrzewska  1 , Agnieszka Kij  1 , Maria Walczak  1 , Stefan Chlopicki  2
Affiliations
Comparative Study

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

Lukasz Mateuszuk et al. J Pharmacol Exp Ther. 2016 Feb.

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 VSports手机版. 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. .

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Figures

None
Graphical abstract
Fig. 1.
Fig. 1.
Effects of MNA and NicA treatment on plasma lipid profile in ApoE/LDLR−/− mice. (A and B) In MNA- and NicA-treated groups, HDL tended to increase (A), whereas LDL tended to decrease (B); however, the differences were statistically insignificant (P ≥ 0.05). (C–E) Very low density lipoprotein (C), total cholesterol (D), and total triglyceride (E) concentrations were unaffected by MNA and NicA treatment. Values are means ± S.E.M. (n = 12). TG, triglyceride; totC, total cholesterol; VLDL, very low density lipoprotein.
Fig. 2.
Fig. 2.
Effects of MNA and NicA treatment on atherosclerotic plaque size in the BCA of ApoE/LDLR−/− mice. (A and C) Representative images show ORO (A) and OMSB (C) staining of plaques in the BCA at various distance from the aortic arch. (B and D) Summarized results show atherosclerotic plaque area estimated on the basis of ORO (B) and OMSB (D) staining, normalized to vessel area for the entire serial sections of the BCA. Values are means ± S.E.M. (n = 12). *P ≤ 0.05 versus untreated control.
Fig. 3.
Fig. 3.
Effects of MNA and NicA treatment on macrophage content in plaques of the BCA in ApoE/LDLR−/− mice. (A and C) Representative images show anti-CD68 (A) and anti-MAC3 (C) immunostainings of plaque area in BCA at various distances from the aortic arch. (B and D) Results of macrophage staining demonstrate a reduction in mean CD68-specific plaque area in MNA- and NicA-treated mice versus untreated control (B) and reduction in mean MAC-specific plaque area, but only in MNA- treated mice (D). Values are means ± S.E.M. (n = 12). *P ≤ 0.05 versus untreated control.
Fig. 4.
Fig. 4.
Results of IR imaging of plaque biochemical content in the BCA. (A) Representative microphotographs of the cross-sections of BCAs taken from control (top), MNA-treated (middle), and NicA-treated (bottom) ApoE/LDLR−/− mice, with spectroscopic images in the ranges of 1700 to 1600 cm−1 (amide I, proteins), 1770 to 1710 cm−1 (esters and triglycerides), and 3000 to 2800 cm−1 (lipids and proteins). (B) Representative FT-IR spectrum of a murine aortic tissue. Arrows indicate bands used to map the distribution of major plaque components. (C) Plaque lipid content of MNA- and NicA-treated mice shown as a percentage of plaque lipid content from the control group. Values are means ± S.E.M. (n = 12). *P ≤ 0.05.
Fig. 5.
Fig. 5.
Effects of MNA and NicA on PGI2 and nitrate/nitrite production by the thoracic aorta (A) Concentration of 6-keto-PGF1α in effluent samples taken from incubated ex vivo aortic rings, with or without the presence of COX inhibitors DUP-697 and indomethacin. (B and C) Concentration of nitrite (B) and nitrate (C) released by aortic rings taken from MNA- and NicA-treated mice and incubated with or without calcium ionophore. Values are means ± S.E.M. (n = 6). *P ≤ 0.05 and **P ≤ 0.01 versus untreated control,
Fig. 6.
Fig. 6.
Effects of MNA and NicA on PGI2/TXB2 metabolite and nitrate/nitrite concentrations in urine. (A) Results of LC-MS/MS analysis of 2,3-dinor-6-keto-PGF1α and 2,3-dinor-TXB2 in urine samples. (B) Results of HPLC-based measurement of urinary nitrite and nitrate. Values are means ± S.E.M. (n = 6). *P ≥ 0.05.
Fig. 7.
Fig. 7.
Effects of MNA and NicA on TXB2 and TNFα release, assessed in ex vivo full blood assay. (A) Results of TXB2 measurement after 30 and 60 minutes of activation. Data were normalized to 105 platelet counts. (B) Concentration of TNFα in blood samples after 60 minutes of activation. Values are means ± S.E.M. (n = 6). *P ≤ 0.05; **P ≤ 0.01 versus untreated control.
Fig. 8.
Fig. 8.
Effects of MNA and NicA on the concentration of NicA metabolites in urine and plasma. (A) Results of LC-MS/MS measurement of NicA and NA and MNA plus Met-4Pyr plus Met-2Pyr concentration in urine. Values are means ± S.E.M. (n = 6). *P ≤ 0.05; **P ≤ 0.01 versus untreated control. (B) Diagram showing the NA/MNA ratio in plasma samples based on LC-MS/MS measurement of NA, MNA, Met-2Pyr, and Met-4Pyr in plasma samples taken from untreated control, MNA-, and NicA-treated mice. Values are means ± S.E.M. (n = 6). **P ≤ 0.01 versus MNA-treated group.
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References

    1. Aksoy S, Szumlanski CL, Weinshilboum RM. (1994) Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J Biol Chem 269:14835–14840. - PubMed
    1. Bartuś M, Łomnicka M, Kostogrys RB, Kaźmierczak P, Watała C, Słominska EM, Smoleński RT, Pisulewski PM, Adamus J, Gebicki J, et al. (2008) 1-Methylnicotinamide (MNA) prevents endothelial dysfunction in hypertriglyceridemic and diabetic rats. Pharmacol Rep 60:127–138. - PubMed
    1. Belenky P, Bogan KL, Brenner C. (2007) NAD+ metabolism in health and disease. Trends Biochem Sci 32:12–19. - "VSports最新版本" PubMed
    1. Bhardwaj SS, Chalasani N. (2007) Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 11:597–613, vii. - PMC - PubMed
    1. Bryniarski K, Biedron R, Jakubowski A, Chlopicki S, Marcinkiewicz J. (2008) Anti-inflammatory effect of 1-methylnicotinamide in contact hypersensitivity to oxazolone in mice; involvement of prostacyclin. Eur J Pharmacol 578:332–338. - PubMed

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