title: Protective effects of 10-nitro-oleic acid in a hypoxia-induced murine model of pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO2) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO2 treatment. Moreover, OA-NO2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO2. In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO2.Our results show that the oleic acid nitroalkene derivative OA-NO2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO2 represents a potential therapeutic agent for the treatment of PAH.
authors: 1 Heart Center, University of Cologne, Cologne, Germany.
authors: Anna
authors: A
authors: Klinke
authors: Annika
authors: A
authors: Möller
authors: Michaela
authors: M
authors: Pekarova
authors: Thorben
authors: T
authors: Ravekes
authors: Kai
authors: K
authors: Friedrichs
authors: Matthias
authors: M
authors: Berlin
authors: Katrin M
authors: KM
authors: Scheu
authors: Lukas
authors: L
authors: Kubala
authors: Hana
authors: H
authors: Kolarova
authors: Gabriela
authors: G
authors: Ambrozova
authors: Ralph T
authors: RT
authors: Schermuly
authors: Steven R
authors: SR
authors: Woodcock
authors: Bruce A
authors: BA
authors: Freeman
authors: Stephan
authors: S
authors: Rosenkranz
authors: Stephan
authors: S
authors: Baldus
authors: Volker
authors: V
authors: Rudolph
authors: Tanja K
authors: TK
authors: Rudolph
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000503:physiopathology*; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009829:Oleic Acids / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism
chemical_list: C521487:10-nitro-oleic acid; D009829:Oleic Acids; D012333:RNA, Messenger; D013481:Superoxides; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: hypoxia; inflammation; nitro-fatty acids; pulmonary arterial hypertension