title: High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation.
abstract: OBJECTIVE
  Diabetes is a major risk factor for cardiovascular diseases. Circulating endothelial microparticles (EMP) are increased in diabetic patients, but their potential contribution in atherogenesis is unclear. We sought to determine the role of EMP derived under high glucose conditions in the development of atherosclerosis.
  
  
  RESULTS
  EMP were generated from human coronary endothelial cells (HCAEC) exposed to high glucose concentrations in order to mimic diabetic conditions. These EMP were defined as 'injured' EMP (iEMP) and their effects were compared with EMP generated from 'healthy' untreated HCAEC. iEMP injection significantly impaired endothelial function in ApoE(-/-) mice compared with EMP and vehicle treatment. Immunofluorescent experiments showed increased macrophage infiltration and adhesion protein expression in atherosclerotic lesions of iEMP-treated ApoE(-/-) mice compared with controls. To further investigate the underlying mechanism of iEMP-induced vascular inflammation, additional in vitro experiments were performed. iEMP, but not EMP, induced activation of HCAEC in a time- and dose-dependent manner and increased monocyte adhesion. Further experiments demonstrated that iEMP induced activation of HCAEC by phosphorylation of p38 into its biologically active form phospho-p38. Inhibition of p38 activation abrogated iEMP-dependent induction of adhesion proteins and monocyte adhesion on HCAEC. Moreover, we could demonstrate that iEMP show increased NADPH oxidase activity and contain significantly higher level of reactive oxygen species (ROS) than EMP. iEMP triggered ROS production in HCAEC and thereby activate p38 in an ROS-dependent manner.
  
  
  CONCLUSIONS
  High glucose condition increases NADPH oxidase activity in endothelial microparticles that amplify endothelial inflammation and impair endothelial function by promoting activation of the endothelium. These findings provide new insights into the pathogenesis of diabetes-associated atherosclerosis.
authors: Department of Internal Medicine II, University Hospital Bonn, Rheinische Friedrich-Wilhelms University, 53105 Bonn, Germany.
authors: Felix
authors: F
authors: Jansen
authors: Xiaoyan
authors: X
authors: Yang
authors: Bernardo S
authors: BS
authors: Franklin
authors: Marion
authors: M
authors: Hoelscher
authors: Theresa
authors: T
authors: Schmitz
authors: Jörg
authors: J
authors: Bedorf
authors: Georg
authors: G
authors: Nickenig
authors: Nikos
authors: N
authors: Werner
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D055252:Cell-Derived Microparticles / Q000201:enzymology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D019255:NADPH Oxidases / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases