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Cardiovascular Research 2007 76(3):494-505; doi:10.1016/j.cardiores.2007.07.017
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Copyright © 2007, European Society of Cardiology

Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-{alpha} associated with induction of angiopoietin-2*

Simone H. Mangan, Ann Van Campenhout, Catherine Rush and Jonathan Golledge*

Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, 4811 Australia

*Corresponding author. Tel.: +61 07 4781 4730; fax: +61 07 4781 6986. jonathan.golledge{at}jcu.edu.au

Objective Osteoprotegerin (OPG) and osteopontin (OPN) have been identified within unstable atherosclerosis and circulating concentrates have been linked to cardiovascular events. We studied the influence of OPG and OPN on endothelial adhesion molecule expression and monocyte binding.

Methods Resting or tumor necrosis factor (TNF-{alpha}) activated human endothelial cells were incubated with OPG (0, 0.5, 5, and 10 ng/mL) or OPN (0, 2.5, 10 and 50 nmol/L). The expression of endothelial genes and proteins was investigated with the Oligo GEArray microarray series, multiplexed gene expression analysis, flow cytometry, ELISA and immunohistochemistry. Monocyte-binding studies were carried out using fluorescently labeled THP-1 cells and analysed by flow cytometry.

Results OPG but not OPN stimulated a dose-dependent increase in the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin by endothelial cells in the presence of TNF-{alpha} (p≤0.05) which was reflected by enhanced binding of THP-1 monocytes. In the absence of TNF-{alpha}, OPG had no significant effect on adhesion molecule expression but upregulated angiopoietin-2. When the induction of angiopoietin-2 was inhibited using interfering RNA the ability of OPG to upregulate adhesion molecules in the presence of TNF-{alpha} was abolished. OPN did not effect adhesion molecule expression by resting or activated endothelial cells.

Conclusion OPG upregulates angiopoietin-2 in human endothelial cells sensitizing them to the effects of TNF-{alpha}. These findings suggest a mechanism by which OPG may stimulate inflammation in atheroma and thereby promote the progression and complications of atherosclerosis.

KEYWORDS Arteries; Atherosclerosis; Gene array analysis; Gene expression; Inflammation

* Funding — The British Journal of Surgery, The National Health and Medical Research Council (379600) and The National Institute of Health (R01 HL080010-–01) supported this work. JG is supported by Practitioner Fellowships from the NHMRC, Australia (431503).


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