RGD Reference Report - Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis. - Rat Genome Database

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Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis.

Authors: Mateuszuk, Łukasz  Khomich, Tamara I  Słomińska, Ewa  Gajda, Mariusz  Wójcik, Luiza  Łomnicka, Magdalena  Gwóźdź, Pawel  Chłopicki, Stefan 
Citation: Mateuszuk Ł, etal., Pharmacol Rep. 2009 Jan-Feb;61(1):76-85. doi: 10.1016/s1734-1140(09)70009-x.
RGD ID: 401794447
Pubmed: PMID:19307695   (View Abstract at PubMed)
DOI: DOI:10.1016/s1734-1140(09)70009-x   (Journal Full-text)

Nicotinamide N-methyltrasferase (NMMT) catalyzes the conversion of nicotinamide (NA) to 1-methylnicotinamide (MNA). Recent studies have reported that exogenous MNA exerts anti-thrombotic and anti-inflammatory activity, suggesting that endogenous NMMT-derived MNA may play a biological role in the cardiovascular system. In the present study, we assayed changes in hepatic NNMT activity and MNA plasma levels along the progression of atherosclerosis in apoE/LDLR(-/-) mice, as compared to age-matched wild-type mice. Atherosclerosis progression in apoE/LDLR(-/-) mice was quantified in aortic root, while hepatic NNMT activity and MNA plasma concentrations were concomitantly measured in 2-, 3-, 4-, and 6-month-old mice. In apoE/LDLR(-/-) mice, atherosclerotic plaques developed in the aortic roots beginning at the age of 3 months and gradually increased in size, macrophage content, and inflammation intensity over time, as detected by Oil-Red O staining, CD68 immunostaining, and in situ zymography (MMP2/MMP9 activity). Hepatic NNMT activity was upregulated approximately two-fold in apoE/LDLR(-/-) mice by the age of 2 months, as compared to wild-type mice (1.03 +/- 0.14 vs. 0.64 +/- 0.23 pmol/min/mg, respectively). MNA plasma concentrations were also elevated approximately two-fold (0.30 +/- 0.13 vs. 0.17 +/- 0.04 micromol/l, respectively). As atherosclerosis progressed, hepatic NMMTactivity and MNA plasma concentrations increased five-fold in 6-month-old apoE/LDLR(-/-) mice at the stage of advanced atherosclerotic plaques (NMMT activity: 2.29 +/- 0.34 pmol/min/mg, MNA concentration: 1.083 +/- 0.33 micromol/l). In summary, the present study demonstrated that the progression of vascular inflammation and atherosclerosis was associated with the upregulation of hepatic NNMT activity and subsequent increase in endogenous MNA plasma levels. Given the anti-thrombotic and anti-inflammatory properties of exogenous MNA, robust activation of an endogenous NA-MNA pathway in atherosclerosis may play an important compensatory role.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
atherosclerosis disease_progressionISONnmt (Mus musculus)401794447; 401794447protein:increased activity:liver (mouse)RGD 
atherosclerosis disease_progressionIEP 401794447protein:increased activity:liver (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Nnmt  (nicotinamide N-methyltransferase)

Genes (Mus musculus)
Nnmt  (nicotinamide N-methyltransferase)

Genes (Homo sapiens)
NNMT  (nicotinamide N-methyltransferase)


Additional Information