Iron Chelators Inhibit VCAM-1 Expression in Human Dermal Microvascular Endothelial Cells

Abstract

Vascular cell adhesion molecule (VCAM)-1 expression may be coupled to redox-sensitive regulatory pathways, and iron may play a role in generation of reactive oxygen species that participate in these signaling pathways. To investigate the role of iron in TNF alpha-induced VCAM-1 gene expression, human dermal microvascular endothelial cells (HDMEC) were stimulated with TNF alpha in the presence of iron chelators and examined for expression of VCAM-1. The iron chelators dipyridyl (DP) and desferoxamine (DFO) inhibited VCAM-1 protein and mRNA induction in a concentration- and time-dependent manner. The induction of VCAM-1 was not inhibited by nonmetal binding reactive oxygen species (ROS) scavengers, implying a direct effect of iron in the expression of these adhesion molecules. The effect of iron was mediated at the level of gene transcription since pretreatment with DP abrogated the TNF alpha-mediated up-regulation of VCAM-1 heterogeneous nuclear RNA. Pretreatment of HDMEC with DP prior to TNFalpha treatment had no effect on p65 nuclear localization, DNA binding, or serine phosphorylation. DP pretreatment inhibited TNF alpha- and IFN gamma-mediated interferon regulatory factor 1 (IRF-1) protein expression, although restoration of IRF-1 expression failed to reconstitute VCAM-1 expression. DP treatment also blocked VCAM-1 induction in human umbilical vein endothelium and blocked induction of a host of NF-kB activated genes in HDMEC including ICAM-1, IL-8, and tissue factor. I kappa B alpha, an NF-kappa B inducible and constitutively accessible gene not requiring chromatin remodeling for transcription, was not affected by DP treatment. These data suggest that iron plays a critical role in TNF alpha mediated VCAM-1 induction in HDMEC, and the target for iron effects may be IRF-1, NF-kappa B, and potentially chromatin remodeling.

Phenyl Methimazole Inhibits TNF-α-Induced VCAM-1 Expression in an IFN Regulatory Factor-1-Dependent Manner and Reduces Monocytic Cell Adhesion to Endothelial Cells

“…A previous study has shown that hyperosmotic stimuli can inhibit TNF-␣-induced VCAM-1 expression in an IRF-1-dependent manner (38). It has also been reported that metal ion chelators inhibit cytokine-induced VCAM-1 expression and perhaps inhibit IRF-1 induction or activity (39). However, to our knowledge our study is the first clear demonstration of a compound that can inhibit TNF-␣-induced VCAM-1 expression in an IRF-1-dependent manner and reduce monocytic cell adhesion to endothelial cells.…”

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

“…1 [8,74,94]. 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).…”