title: Hypoxia-induced endothelial dysfunction in apolipoprotein E-deficient mice; effects of infliximab and L-glutathione.
abstract: OBJECTIVE
  Obstructive sleep apnoea (OSA) has been implicated as a risk factor for atherosclerosis. The aim of our study was to examine the effects of chronic intermittent hypoxia in apoE-/- mice serving as model of OSA on endothelial dysfunction and oxidative stress and to evaluate the reversibility of hypoxia-induced changes under anti-inflammatory infliximab and anti-oxidative l-glutathione.
  
  
  METHODS
  ApoE-/- mice were divided into 4 groups (n = 9 each): 1. intermittent hypoxia 8 h/day for 6 weeks, 2. intermittent hypoxia + injections of infliximab, 3. intermittent hypoxia + injections of l-glutathione, 4. normoxia = control.
  
  
  RESULTS
  Endothelial function was impaired under hypoxia compared to control. Application of infliximab and l-glutathione improved it to a level of control. The percentage of endothelial microparticles increased under hypoxia compared to other groups. Levels of NADPH oxidase 2-derived reactive oxygen species were approximately 9 times higher in the hypoxia group. The number of sca-1/flk-1+ endothelial progenitor cells was higher in bone marrow and lower in blood under hypoxia vs. other groups. Stromal cell derived factor-1alpha- and matrix metalloproteinase-9-dependent release of these cells from bone marrow was attenuated under hypoxia. The number of DilacLDL+/lectin + early outgrowth progenitor cells and that of colony forming units from these cells were higher under hypoxia. Atherosclerotic plaques in the aorta were more frequent under hypoxia and control in comparison with both drug groups.
  
  
  CONCLUSIONS
  Intermittent hypoxia contributes to endothelial dysfunction by the local increase in reactive oxygen species and reduction of the peripheral repair capacity. Infliximab and l-glutathione prevent hypoxia-induced vascular and extravascular changes.
authors.affiliation: Department of Internal Medicine II - Cardiology, Pulmonology, University of Bonn, Bonn, Germany. Electronic address: Izabela.Tuleta@ukb.uni-bonn.de.
authors.forename: Izabela
authors.initials: I
authors.lastname: Tuleta
authors.affiliation: Department of Internal Medicine II - Cardiology, Pulmonology, University of Bonn, Bonn, Germany.
authors.forename: Carolina Nunes
authors.initials: CN
authors.lastname: França
authors.affiliation: Department of Physiology I, University of Bonn, Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Department of Physiology I, University of Bonn, Bonn, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fleischmann
authors.affiliation: Department of Internal Medicine II - Cardiology, Pulmonology, University of Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Department of Internal Medicine II - Cardiology, Pulmonology, University of Bonn, Bonn, Germany.
authors.forename: Nikos
authors.initials: N
authors.lastname: Werner
authors.affiliation: Department of Internal Medicine II - Cardiology, Pulmonology, University of Bonn, Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Skowasch
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001018:Aortic Diseases / Q000209:etiology; D001057:Apolipoproteins E / Q000172:deficiency; D001853:Bone Marrow / Q000503:physiopathology; D055252:Cell-Derived Microparticles; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D066026:Endothelial Progenitor Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005978:Glutathione / Q000627:therapeutic use*; D000860:Hypoxia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D000069285:Infliximab; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000209:etiology; D017382:Reactive Oxygen Species / Q000097:blood; D020181:Sleep Apnea, Obstructive; D013154:Spleen / Q000166:cytology
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000975:Antioxidants; D001057:Apolipoproteins E; D017382:Reactive Oxygen Species; D000069285:Infliximab; D005978:Glutathione
keywords: Atherosclerosis; Endothelium; Free radicals; Hypoxia; Progenitor cells