title: Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha.
abstract: Pulmonary hypertension (PH), associated with imbalance in vasoactive mediators and massive remodeling of pulmonary vasculature, represents a serious health complication. Despite the progress in treatment, PH patients typically have poor prognoses with severely affected quality of life. Asymmetric dimethyl arginine (ADMA), endogenous inhibitor of endothelial nitric oxide synthase (eNOS), also represents one of the critical regulators of pulmonary vascular functions. The present study describes a novel mechanism of ADMA-induced dysfunction in human pulmonary endothelial and smooth muscle cells. The effect of ADMA was compared with well-established model of hypoxia-induced pulmonary vascular dysfunction. It was discovered for the first time that ADMA induced the activation of signal transducer and activator of transcription 3 (STAT3) and stabilization of hypoxia inducible factor 1α (HIF-1α) in both types of cells, associated with drastic alternations in normal cellular functions (e.g., nitric oxide production, cell proliferation/Ca(2+) concentration, production of pro-inflammatory mediators, and expression of eNOS, DDAH1, and ICAM-1). Additionally, ADMA significantly enhanced the hypoxia-mediated increase in the signaling cascades. In summary, increased ADMA may lead to manifestation of PH phenotype in human endothelial and smooth muscle cells via the STAT3/HIF-1α cascade. Therefore this signaling pathway represents the potential pathway for future clinical interventions in PH.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic. Electronic address: pekarovam@ibp.cz.
authors.forename: Michaela
authors.initials: M
authors.lastname: Pekarova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Adolf
authors.initials: A
authors.lastname: Koudelka
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Kolarova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ambrozova
authors.affiliation: Department of Experimental Cardiology, University Hospital of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Cerna
authors.affiliation: Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3058/10, 616 00 Brno, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kadlec
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., BIOCEV, Videnska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Maria
authors.initials: M
authors.lastname: Trundova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Sindlerova Svihalkova
authors.affiliation: Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3058/10, 616 00 Brno, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Kuchta
authors.affiliation: Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3058/10, 616 00 Brno, Czech Republic.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Kuchtova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic.
authors.forename: Antonin
authors.initials: A
authors.lastname: Lojek
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic; International Clinical Research Center - Center of Biomolecular and Cellular Engineering, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C573420:ICAM1 protein, human; D018836:Inflammation Mediators; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase; D002118:Calcium
keywords: Asymmetric dimethyl arginine; Human pulmonary artery endothelial cell; Human pulmonary artery smooth muscle cell; Hypoxia; Pulmonary hypertension