title: Apolipoprotein E3- and nitric oxide-dependent modulation of endothelial cell inflammatory responses.
abstract: OBJECTIVE
  Although apolipoprotein E3 (apoE3) is known to be atheroprotective, its mechanisms of protection in endothelial cells remain unclear.
  
  
  RESULTS
  Cultured human aortic endothelial cells were stimulated with tumor necrosis factor (TNF)-alpha in the presence of human recombinant apoE3 solubilized in dimyristoyl phosphatidylcholine liposomes. Using flow cytometry and real-time polymerase chain reaction, a significant increase of inflammatory cell adhesion proteins (vascular cell adhesion molecule-1 and E-Selectin), and MCP-1, interleukin-8, and intercellular adhesion molecule-1 gene expression was observed within 5 hours of TNF-alpha exposure, which was markedly attenuated in cells coincubated with apoE3. Treatment with apoE4 resulted in increased inflammatory gene expression relative to either TNF treatment alone or TNF + apoE3 treatment. NO synthase inhibition experiments demonstrated NO to be an active participant in the actions of both TNF and apoE. To clarify the role of NO, dose-response experiments were performed with 0.03 to 300 micromol/L DEA-NONOate. Using flow cytometry and real-time polymerase chain reaction, a modulatory role of NO in TNF-induced endothelial cell activation was observed.
  
  
  CONCLUSIONS
  These data suggest a role of vascular wall apoE3 to balance the intracellular redox state in injured endothelial cells via NO-dependent pathways.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, School of Medicine, University of California, Davis, USA. amullick@scripps.edu
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Powers
authors.forename: Rama S
authors.initials: RS
authors.lastname: Kota
authors.forename: Sarada D
authors.initials: SD
authors.lastname: Tetali
authors.forename: Jason P
authors.initials: JP
authors.lastname: Eiserich
authors.forename: John C
authors.initials: JC
authors.lastname: Rutledge
mesh_terms: D053318:Apolipoprotein E3 / Q000235:genetics / Q000502:physiology*; D053327:Apolipoprotein E4 / Q000494:pharmacology; D001167:Arteritis / Q000503:physiopathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010084:Oxidation-Reduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019040:E-Selectin; D006834:Hydrazines; D016209:Interleukin-8; D020030:Nitric Oxide Donors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine