title: Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition.
abstract: Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response.
  
  
  
  The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays.
  
  
  
  OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3.
  
  
  
  The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation.
  
  
  
  These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.
authors.affiliation: Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65, Brno, Czech Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ambrozova
authors.affiliation: Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65, Brno, Czech Republic.
authors.forename: Tana
authors.initials: T
authors.lastname: Fidlerova
authors.affiliation: Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, 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: Hana
authors.initials: H
authors.lastname: Verescakova
authors.affiliation: Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, 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: Adolf
authors.initials: A
authors.lastname: Koudelka
authors.affiliation: Faculty of Science, Institute of Experimental Biology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic; Heart Centre, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Rudolph
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: Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65, Brno, Czech Republic; International Clinical Research Center - Center of Biomolecular and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
authors.affiliation: Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65, Brno, Czech Republic; International Clinical Research Center - Center of Biomolecular and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic. Electronic address: pekarovam@ibp.cz.
authors.forename: Michaela
authors.initials: M
authors.lastname: Pekarova
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009829:Oleic Acids / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C521487:10-nitro-oleic acid; D016328:NF-kappa B; D009829:Oleic Acids; D050791:STAT Transcription Factors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Endothelial cells; Endothelial-mesenchymal transition; Macrophages; Nitro-fatty acids; Nitro-oleic acid; Vascular inflammation