title: Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension.
abstract: 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. Here we examined changes in NNMT-MNA pathway in PAH in rats and humans.
  
  
  
  PAH 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.
  
  
  
  MCT-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.
  
  
  
  Progression 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.
authors: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, Krakow, Poland.|Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, Krakow, Poland.
authors: Andrzej
authors: A
authors: Fedorowicz
authors: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, Krakow, Poland.
authors: Łukasz
authors: Ł
authors: Mateuszuk
authors: Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital in Krakow, Pradnicka 80, Kraków, Poland.
authors: Grzegorz
authors: G
authors: Kopec
authors: Institute of Nuclear Physics Polish Academy of Sciences, PL-31342, Kraków, Poland.
authors: Tomasz
authors: T
authors: Skórka
authors: Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, Gdańsk, Poland.
authors: Barbara
authors: B
authors: Kutryb-Zając
authors: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, Krakow, Poland.
authors: Agnieszka
authors: A
authors: Zakrzewska
authors: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, Krakow, Poland.|Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors: Maria
authors: M
authors: Walczak
authors: Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, Krakow, Poland.
authors: Andrzej
authors: A
authors: Jakubowski
authors: Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, Krakow, Poland.
authors: Magdalena
authors: M
authors: Łomnicka
authors: Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, Gdańsk, Poland.
authors: Ewa
authors: E
authors: Słomińska
authors: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, Krakow, Poland. stefan.chlopicki@jcet.eu.|Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, Krakow, Poland. stefan.chlopicki@jcet.eu.
authors: Stefan
authors: S
authors: Chlopicki
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D019332:Endothelin-1 / Q000097:blood; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016686:Monocrotaline; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D018497:Ventricular Dysfunction, Right / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D016278:Ventricular Function, Right
chemical_list: D019332:Endothelin-1; D009536:Niacinamide; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D016686:Monocrotaline; D011464:Epoprostenol; C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase; C000625139:Nnmt protein, rat; C024058:N(1)-methylnicotinamide
keywords: Idiopathic pulmonary hypertension; Isolated lungs; Monocrotaline; Nicotinamide N-methyltransferase; Prostacyclin, Pulmonary endothelial dysfunction; Pulmonary hypertension