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


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

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dc.contributor.author Fedorowicz, Andrzej [SAP20002236] pl
dc.contributor.author Mateuszuk, Łukasz [SAP14003983] pl
dc.contributor.author Kopeć, Grzegorz [SAP20010762] pl
dc.contributor.author Skórka, Tomasz pl
dc.contributor.author Kutryb-Zajac, Barbara pl
dc.contributor.author Zakrzewska, Agnieszka [SAP14003150] pl
dc.contributor.author Walczak, Maria [SAP20001007] pl
dc.contributor.author Jakubowski, Andrzej [SAP20001317] pl
dc.contributor.author Łomnicka, Magdalena [SAP20007512] pl
dc.contributor.author Słomińska, Ewa pl
dc.contributor.author Chłopicki, Stefan [SAP20000969] pl
dc.date.accessioned 2016-12-19T09:10:30Z
dc.date.available 2016-12-19T09:10:30Z
dc.date.issued 2016 pl
dc.identifier.issn 1465-9921 pl
dc.identifier.uri http://ruj.uj.edu.pl/xmlui/handle/item/34024
dc.language eng pl
dc.rights Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa *
dc.rights.uri http://creativecommons.org/licenses/by/4.0/pl/legalcode *
dc.title Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension pl
dc.type JournalArticle pl
dc.description.physical 1-13 pl
dc.abstract.en Background: 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. Methods: PAH in rats was induced by a single subcutaneous injection of MCT (60mg/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. Results: 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. Conclusions: 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. pl
dc.subject.en idiopathic pulmonary hypertension pl
dc.subject.en isolated lungs pl
dc.subject.en monocrotaline pl
dc.subject.en nicotinamide N-methyltransferase pl
dc.subject.en prostacyclin pl
dc.subject.en pulmonary endothelial dysfunction pl
dc.subject.en pulmonary hypertension pl
dc.description.volume 17 pl
dc.description.points 35 pl
dc.identifier.doi 10.1186/s12931-016-0423-7 pl
dc.identifier.eissn 1465-993X pl
dc.title.journal Respiratory Research pl
dc.language.container eng pl
dc.affiliation Pion Prorektora ds. badań naukowych i funduszy strukturalnych : Jagiellońskie Centrum Rozwoju Leków pl
dc.affiliation Wydział Lekarski : Zakład Farmakologii pl
dc.affiliation Wydział Lekarski : Instytut Kardiologii pl
dc.affiliation Pion Rektora : Jagiellońskie Centrum Rozwoju Leków pl
dc.subtype Article pl
dc.identifier.articleid 108 pl
dc.rights.original CC-BY; otwarte czasopismo; ostateczna wersja wydawcy; w momencie opublikowania; 0; pl
dc.identifier.project ROD UJ / P pl
dc.cm.id 79358
.pointsMNiSW [2016 A]: 35

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Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa Except where otherwise noted, this item's license is described as Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa