on October 14, 2004
Published online before print October 14, 2004, doi: 10.1161/01.ATV.0000147406.00871.b3
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Submitted on June 14, 2004
Accepted on September 9, 2004
Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells
Apriliana E.R. Kartikasari ;
From the Eijkman-Winkler Center for Medical Microbiology (A.E.R.K., N.A.G., F.L.J.V., H.v.K.-R., B.S.v.A., J.J.M.M.), Infectious Diseases, and Inflammation and Eijkman Graduate School for Immunology and Infectious Diseases, and the Departments of Vascular Medicine (F.L.J.V.) and Internal Medicine (B.S.v.A.), University Medical Center Utrecht, The Netherlands.
* To whom correspondence should be addressed. E-mail: jmarx{at}azu.nl.
Objective--Elevated iron stores and high plasma iron concentration have been linked to an increased risk of atherosclerosis. Iron may thereby affect the interaction of monocytes to endothelium, an initial event in the formation of atherosclerotic plaques.
Methods and Results--Addition of 10 µmol/L non-transferrin-bound iron to the incubation medium caused a 2-fold increase in monocyte adhesion to human umbilical vein endothelial cells (HUVECs). A concordant increase in the expression of the following adhesion molecules was observed: vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial selectin on HUVECs as well as very late antigen-4, and lymphocyte function-associated antigen-1 on monocytes. The inclusion of either deferiprone or salicylaldehyde isonicotinoylhydrazone counteracted these effects. Intracellular iron chelation by deferoxamine was completed only after 10 hours of incubation, shown by reversal of iron-quenched intracellular calcein signal, and concurrently the effects of iron were blunted. The membrane-impermeable chelator, diethylenetriamine pentaaceticacid, failed to negate iron effects, even after 48 hours of treatment. Furthermore, only membrane-permeable superoxide or hydroxyl radical scavengers were capable of preventing HUVEC activation by iron.
Conclusions--Non-transferrin-bound iron increases the level of intracellular labile iron, which promotes monocyte recruitment to endothelium and may thereby contribute to the pathogenesis of atherosclerosis. Iron-induced adhesion molecule expression was observed, and this event may involve the production of oxygen radicals.
Key words: iron • atherosclerosis • monocytes • endothelium • adhesion molecules
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