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 2/2 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 F 1a and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B 2 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 2/2 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.

Functional and Biochemical Endothelial Profiling In Vivo in a Murine Model of Endothelial Dysfunction; Comparison of Effects of 1-Methylnicotinamide and Angiotensin-converting Enzyme Inhibitor

“…Indeed, in our recent study anti-atherosclerotic effects of MNA in ApoE/LDLR -/- mice, including the inhibition of inflammatory burden in plaques, diminished systemic inflammation, diminished platelet activation that were associated with an improvement in PGI 2 and NO-dependent endothelial function. These results support the notion that pronounced effects of MNA on endothelial function could contribute to therapeutic efficacy of MNA (Mateuszuk et al, 2016). However, in none of the previous experimental studies of MNA was endothelial function assessed in vivo , but only in ex vivo vascular preparation (Bartuś et al, 2008; Mateuszuk et al, 2016).…”

“…These results support the notion that pronounced effects of MNA on endothelial function could contribute to therapeutic efficacy of MNA (Mateuszuk et al, 2016). However, in none of the previous experimental studies of MNA was endothelial function assessed in vivo , but only in ex vivo vascular preparation (Bartuś et al, 2008; Mateuszuk et al, 2016). …”

“…Altogether, our results suggest that MNA displayed a similar pattern of vasoprotective activity as perindopril, a representative of ACE-Is, and both compounds affected ACE/Ang II-ACE2/Ang-(1–7) balance and L -Arg/ADMA ratio that could contribute to their vasoprotective effects. Given that correction of endothelial function by ACE-Is contributes significantly to their clinical benefits and their anti-inflammatory, anti-thrombotic, anti-diabetic, and vasoprotective actions reported in numerous experimental and clinical papers (Chłopicki and Gryglewski, 2005), the findings of endothelial profile of MNA being similar to perindopril in in vivo settings bring important novel perspectives to understanding the therapeutic efficacy of MNA reported previously (Gebicki et al, 2003; Wozniacka et al, 2005; Chlopicki et al, 2007; Bartuś et al, 2008; Bryniarski et al, 2008; Brzozowski et al, 2008; Watała et al, 2009; Sternak et al, 2010; Przyborowski et al, 2015; Blazejczyk et al, 2016; Jakubowski et al, 2016; Mateuszuk et al, 2016). …”

“…Doses of compounds used in this study were based on our previous published (Chlopicki et al, 2007; Mateuszuk et al, 2016) and unpublished studies, for MNA and perindopril, respectively. Two groups of 4-month-old ApoE/LDLR -/- mice were left untreated (as control groups) for 1 and 2 months, respectively.…”

“…MNA was demonstrated to have hepatoprotective activity against concanavalin A-induced liver injury through the downregulation of IL-4 and TNF-α signaling (Sternak et al, 2010; Jakubowski et al, 2016), and to inhibit metastasis formation in a murine model of metastatic mammary gland cancer (4T1) in BALB/c mice (Blazejczyk et al, 2016). Interestingly, 1-MNA has also been shown to restore endothelial function in diabetic hypertriglycemic rats (Bartuś et al, 2008) analyzed ex vivo in isolated aorta, suggesting that the improvement in endothelial function may represent an important target of MNA activity and may explain therapeutic efficacy of MNA in various diseases including diabetes (Watała et al, 2009) and atherosclerosis (Mateuszuk et al, 2016). Indeed, in our recent study anti-atherosclerotic effects of MNA in ApoE/LDLR -/- mice, including the inhibition of inflammatory burden in plaques, diminished systemic inflammation, diminished platelet activation that were associated with an improvement in PGI 2 and NO-dependent endothelial function.…”