Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension

Abstract

BackgroundPulmonary arterial hypertension (PAH) is associated with inflammatory response but it is unknown whether it is associated with alterations in NNMT activity and MNA plasma concentration. Here we examined changes in NNMT-MNA pathway in PAH in rats and humans.MethodsPAH in rats was induced by a single subcutaneous injection of MCT (60 mg/kg). Changes in NNMT activity in the lungs and liver (assessed as the rate of conversion of nicotinamide (NA) to MNA), changes in plasma concentration of MNA and its metabolites (analyzed by LC/MS) were analyzed in relation to PAH progression. PAH was characterized by right ventricular hypertrophy (gross morphology), cardiac dysfunction (by MRI), lung histopathology, lung ultrastructure, and ET-1 concentration in plasma. NO-dependent and PGI2-dependent function in isolated lungs was analyzed. In naive patients with idiopathic pulmonary hypertension (IPAH) characterized by hemodynamic and biochemical parameters MNA and its metabolites in plasma were also measured.ResultsMCT-injected rats developed hypertrophy and functional impairment of the right ventricle, hypertrophy of the pulmonary arteries, endothelial ultrastructural defects and a progressive increase in ET-1 plasma concentration—findings all consistent with PAH development. In isolated lung, NO-dependent regulation of hypoxic pulmonary vasoconstriction was impaired, while PGI2 production (6-keto-PGF1α) was increased. NNMT activity increased progressively in the liver and in the lungs following MCT injection, and NNMT response was associated with an increase in MNA and 6-keto-PGF1α concentration in plasma. In IPAH patients plasma concentration of MNA was elevated as compared with healthy controls.ConclusionsProgression of pulmonary hypertension is associated with the activation of the NNMT-MNA pathway in rats and humans. Given the vasoprotective activity of exogenous MNA, which was previously ascribed to PGI2 release, the activation of the endogenous NNMT-MNA pathway may play a compensatory role in PAH.

Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme

“…Significant upregulation of NNMT expression is also seen in the skeletal muscle of patients with various forms of dystrophies and can also be modeled in the mdx mouse, a model Duchenne ‘s muscular dystrophy [57]. Furthermore, experimental liver injury with concavalin A and induction of pulmonary hypertension also increase NNMT expression and activity [58,59]. The increased inflammation in these disease states and injury models is thought to drive the increase in NNMT expression.…”

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

“…NNMT is mainly involved in the biotransformation of drugs and other xenobiotic chemicals (11). Recent studies have demonstrated that NNMT is aberrantly expressed in a number of tumors, suggesting that NNMT serves an important function in tumor development (12,13). Additionally, the serum levels of NNMT were significantly increased in patients with colorectal, lung and renal cell carcinoma compared with those in the control group (10,14,15).…”

High-density lipoprotein cholesterol level and pulmonary artery vasoreactivity in patients with idiopathic pulmonary arterial hypertension

“…These results implicate the possible apolipoprotein pathway in pulmonary vasculopathy associated with endothelial dysfunction. 30,31 In this study, we demonstrated that higher levels of inflammatory markers are associated with lower HDL -C levels; therefore, we speculate that chronic inflammation can mediate the relationship between HDL -C and pulmonary vasoreactivity. Animal and human model studies indicate a significant role of systemic inflammation in the pathogenesis of IPAH.…”