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

Abstract

Abstract: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 mmol/l, respectively). As atherosclerosis progressed, hepatic NMMT activity 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 mmol/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.

SerumN1-Methylnicotinamide Is Associated With Obesity and Diabetes in Chinese

“…It is possible that increased NNMT activity, rather than elevated homocysteine levels, may contribute to low HDL and cardiovascular risk. In fact, hepatic NNMT activity increases by Ͼ2-fold in apolipoprotein-E/LDL receptor double knockout mice compared with that in control mice (25). Further studies are necessary to determine whether inhibition of NNMT activity may increase HDL levels and improve cardiovascular disease.…”

Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity

“…NNMT upregulation has been reported in several neoplasms, such as glioblastoma multiforme ( Markert et al, 2001 ), gastric cancer ( Lim et al, 2006 ), papillary thyroid cancer ( Xu et al, 2003 ), RCC ( Sartini et al, 2006 ), OSCCs ( Sartini et al, 2007 ;Emanuelli et al, 2010 ;Sartini et al, 2012 ), colorectal ( Roessler et al, 2005 ), bladder ( Sartini et al, 2013a ), lung ( Sartini et al, 2013b ), and pancreatic ( Rogers et al, 2006 ) cancers. Moreover, NNMT was found to be overexpressed in atherosclerosis ( Mateuszuk et al, 2009 ), chronic obstructive pulmonary disease (COPD) ( Debigar é et al, 2008 ), and Parkinson ' s disease ( Parsons et al, 2002 ).…”

Nicotinamide N-methyltransferase is overexpressed in prostate cancer and correlates with prolonged progression-free and overall survival times

“…However, abnormal NNMT expression has been identified in several types of tumors, including glioblastoma (16), stomach adenocarcinoma (17), papillary thyroid cancers (18), colorectal cancer (12), hepatocellular carcinoma (19), lung cancer (11) and renal cancer (20), suggesting that NNMT may have a significant role in cancer. Among non-neoplastic disorders, the enhanced expression of NNMT has been detected in chronic obstructive pulmonary disease (21), atherosclerosis (22), and Parkinson’s disease (23). …”