Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells

Abstract

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 mol/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 Ⅲ atherosclerosis Ⅲ monocytes Ⅲ endothelium Ⅲ adhesion molecules A therosclerosis has been associated with several important environmental and genetic risk factors. It is characterized by inflammatory changes leading to plaque formation and, furthermore, to plaque rupture and arterial thrombosis. Transendothelial migration of leukocytes is a fundamental inflammatory mechanism in atherogenesis. 1 This process is partly mediated by the interaction between endothelial adhesion molecules and their ligands on monocytes.Elevated concentrations of adhesion molecules have been observed in human atherosclerotic plaques, including 2 members of the immunoglobulin superfamily of adhesion receptors, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as a member of the selectin family, endothelial selectin (E-Selectin). Moreover, a significant correlation has been found between the degree of macrophage infiltration and endothelial ICAM-1, VCAM-1, and E-selectin expression in atherosclerotic lesions. 2 The infiltration of leukocytes consists of consecutive adhesion-mediated events. The first step of adhesion involves binding of selectins to carbohydrate ligands that triggers tethering of the leukocytes to the activated endothelium along the vessel wall. Arrest and firm adhesion of the leukocytes on activated endothelial cells occur depending on the activat...

Non Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation

“…Experimental cell culture studies had shown that addition of NTBI to human endothelial cell culture increase the surface expression of adhesion molecules and also increase the monocyte adherence to endothelium [95,96]. These consequences can be corrected by addition of iron chelators like desferrioxamine and dipirydyl, which decrease expression of adhesion molecules and monocyte adherence [95,96].…”

The Role of Iron in Diabetes and Its Complications

“…In cell culture models, the addition of NTBI to human endothelial cell cultures increases surface expression of adhesion molecules (101,102) and also increases monocyte adherence to the endothelium. These abnormalities can be corrected by the addition of iron chelators such as desferoxamine and dipirydyl.…”

“…These abnormalities can be corrected by the addition of iron chelators such as desferoxamine and dipirydyl. Such an addition decreases expression of adhesion molecules and monocyte adherence (101)(102)(103). In human studies of end-stage renal disease patients, intravenous iron therapy has been shown to increase vascular and systemic oxidative stress (104 -106), promote atherosclerosis (106), and increase the risk of arterial thrombosis (105).…”

Acute Hypoxia Induces HIF-Independent Monocyte Adhesion to Endothelial Cells through Increased Intercellular Adhesion Molecule-1 Expression: The Role of Hypoxic Inhibition of Prolyl Hydroxylase Activity for the Induction of NF-κB

“…Furthermore, it consists of a transmem-brane region and a very short cytoplasmic tail of only 28 aa. Its role as receptor within the leukocyte-adhesion cascade is very well recognized (22)(23)(24)(25)(26); it was shown that surface ICAM-1 levels on endothelial cells are inducible by cytokines (mostly TNF-a and IL-1b), bacterial LPSs, and redox-sensitive mechanisms (27)(28)(29)(30). ICAM-1 can also be found on the surface of monocytes; however, until now, its known function is limited to Ag presentation to MHC class II-restricted T cells (31,32).…”