Apolipoprotein E3- and nitric oxide-dependent modulation of endothelial cell inflammatory responses.
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.
Mullick
Adam E
AE
Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, School of Medicine, University of California, Davis, USA. amullick@scripps.edu
Powers
Andrew F
AF
Kota
Rama S
RS
Tetali
Sarada D
SD
Eiserich
Jason P
JP
Rutledge
John C
JC
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
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