title: Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction.
abstract: BACKGROUND
  Pulmonary hypertension (PH) represents a serious health complication accompanied with hypoxic conditions, elevated levels of asymmetric dimethylarginine (ADMA), and overall dysfunction of pulmonary vascular endothelium. Since the prevention strategies for treatment of PH remain largely unknown, our study aimed to explore the effect of nitro-oleic acid (OA-NO2), an exemplary nitro-fatty acid (NO2-FA), in human pulmonary artery endothelial cells (HPAEC) under the influence of hypoxia or ADMA.
  
  
  METHODS
  HPAEC were treated with OA-NO2in the absence or presence of hypoxia and ADMA. The production of nitric oxide (NO) and interleukin-6 (IL-6) was monitored using the Griess method and ELISA, respectively. The expression or activation of different proteins (signal transducer and activator of transcription 3, STAT3; hypoxia inducible factor 1α, HIF-1α; endothelial nitric oxide synthase, eNOS; intercellular adhesion molecule-1, ICAM-1) was assessed by the Western blot technique.
  
  
  RESULTS
  We discovered that OA-NO2prevents development of endothelial dysfunction induced by either hypoxia or ADMA. OA-NO2preserves normal cellular functions in HPAEC by increasing NO production and eNOS expression. Additionally, OA-NO2inhibits IL-6 production as well as ICAM-1 expression, elevated by hypoxia and ADMA. Importantly, the effect of OA-NO2is accompanied by prevention of STAT3 activation and HIF-1α stabilization.
  
  
  CONCLUSIONS
  In summary, OA-NO2eliminates the manifestation of hypoxia- and ADMA-mediated endothelial dysfunction in HPAEC via the STAT3/HIF-1α cascade. Importantly, our study is bringing a new perspective on molecular mechanisms of NO2-FAs action in pulmonary endothelial dysfunction, which represents a causal link in progression of PH. Graphical Abstract ᅟ.
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.|International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ambrozova
authors.affiliation: International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.|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.|Faculty of Science, Institute of Experimental Biology, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
authors.forename: Tana
authors.initials: T
authors.lastname: Fidlerova
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, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.|Faculty of Science, Institute of Experimental Biology, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Martiskova
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: Department of Experimental Cardiology, University Hospital of Cologne, Kerpener Str. 62, 50924, Cologne, Germany.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Rudolph
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: 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: Department of Pharmacology and Chemical Biology, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA, 15260, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Woodcock
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA, 15260, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
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, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 612 65, Brno, Czech Republic. pekarovam@ibp.cz.|International Clinical Research Center, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic. pekarovam@ibp.cz.
authors.forename: Michaela
authors.initials: M
authors.lastname: Pekarova
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009829:Oleic Acids / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508600:IL6 protein, human; D015850:Interleukin-6; D009829:Oleic Acids; 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
keywords: Asymmetric dimethylarginine; Human pulmonary artery endothelial cell; Hypoxia; Nitro-oleic acid; Pulmonary hypertension