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

Andrzej Fedorowicz,Grzegorz Kopec,Agnieszka Zakrzewska,Stefan Chlopicki,Łukasz Mateuszuk,Ewa Słomińska,Barbara Kutryb-Zając,Tomasz Skórka,Andrzej Jakubowski,Magdalena Łomnicka,Maria Walczak

doi:10.1186/s12931-016-0423-7

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.

Highlights

Pulmonary arterial hypertension (PAH) is associated with inflammatory response but it is unknown whether it is associated with alterations in Nicotinamide N-methyltransferase (NNMT) activity and MNA plasma concentration
Development of PAH induced by monocrotaline (MCT) As shown in Fig. 1, injection of MCT resulted in severe PAH with 100 % mortality (Fig. 1a)
The progression of PAH was evidenced by remodelling of the small pulmonary arteries, with typical thickening, muscularization and disorganization of the media of the pulmonary arterial wall associated with inflammatory cell infiltration around vessels and in the interstitial lung space (Fig. 1e)

Summary

Introduction

Pulmonary 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. NNMT activity is localized mainly in the liver but has been detected in adipose tissue, kidney, lung, skeletal muscle, heart and brain [1, 2]. Alterations in NNMT expression and activity occurs in number of diseases. Altered NNMT activity was associated with multiple other diseases, for example, Parkinson’s disease, liver cirrhosis, metabolic syndrome and diabetes [5,6,7,8]. NNMT may be either a pathogenetic factor or a protective factor in these diseases. NMMT in adipose tissue was proposed to contribute to insulin resistance and obesity, while NNMT in the liver was protective against diet-induced alterations in metabolism [5, 9]

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