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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:339.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Apolipoprotein E3- and Nitric Oxide–Dependent Modulation of Endothelial Cell Inflammatory Responses

Adam E. Mullick; Andrew F. Powers; Rama S. Kota; Sarada D. Tetali; Jason P. Eiserich; John C. Rutledge

From the Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine (A.E.M., A.F.P., R.S.K., S.D.T., J.C.R.) and the Division of Nephrology (J.P.E.), and the Department of Human Physiology (J.P.E.), School of Medicine, University of California, Davis.

Correspondence to Adam E. Mullick, PhD, The Scripps Research Institute, Department of Immunology, IMM-17, 10550 N. Torrey Pines Road, La Jolla, CA 92037. E-mail amullick{at}scripps.edu

Objective— Although apolipoprotein E3 (apoE3) is known to be atheroprotective, its mechanisms of protection in endothelial cells remain unclear.

Methods and Results— Cultured human aortic endothelial cells were stimulated with tumor necrosis factor (TNF)- 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- 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 µmol/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.

Endothelial-specific effects of apolipoprotein E3 (apoE3), apoE4, and nitric oxide (NO) were assessed with functional and genomic assays of cell inflammation. Herein, we describe a potent antiinflammatory role of apoE3 that is related to modulation of NO. These results have mechanistic implications of the atheroprotective roles of apoE3 and NO.

Key Words: apolipoprotein E • nitric oxide • aortic endothelial cells • atherosclerosis