Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 34, Issue 6, Pages 674-682Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0891-5849(02)01375-8
Keywords
metal ions; cell adhesion molecules; endothelium; signal transduction; atherosclerosis
Funding
- NHLBI NIH HHS [HL-60886] Funding Source: Medline
- NIEHS NIH HHS [ES-11542] Funding Source: Medline
Ask authors/readers for more resources
Endothelial adhesion molecule expression and monocyte recruitment are causal events in human atherosclerosis, and are believed to be caused, in part, by oxidative stress. Because redox-active transition metal ions, such as iron and copper, play an essential role in the generation of free radicals and the initiation and propagation of lipid peroxidation, we hypothesized that transition metal ions may also be involved in endothelial activation. Therefore, we investigated the effects of the intracellular iron-chelator, desferrioxamine (DFO), and the intracellular copper-chelator, neocuproine (NC), on TNFalpha-induced expression of adhesion molecules in human aortic endothelial cells (HAEC). Treatment of HAEC with DFO (0.01-0.1 mM) or NC (0.1 and 0.5 mM) time- and dose-dependently inhibited TNFalpha-induced protein expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). In contrast, iron-saturated DFO and the extracellular copper chelator, bathocuproinedisulfonic acid, had no effect on adhesion molecule expression. DFO and NC also dose-dependently inhibited TNFalpha-induced upregulation of adhesion molecule mRNA levels. Furthermore, treatment of HAEC with 0.5 mM DFO or NC completely inhibited TNFalpha-induced activation of the transcription factor, specificity protein-1 (SP-1), but only partially inhibited or did not affect activation of other transcription factors known to regulate adhesion molecule expression, i.e., nuclear factor kappaB (NFkappaB), activator protein-1 (AP-1), and interferon regulatory factor-1 (IRF-1). Finally, inhibition of endothelial nitric oxide synthase with N-nitro-L-arginine methylester (0.5 mM) did not attenuate the inhibitory effects of the metal ion chelators on adhesion molecule expression. Our data suggest that intracellular, but not extracellular, transition metal ions mediate inflammatory cytokine-induced SP-1 activation and adhesion molecule expression in endothelial cells. (C) 2003 Elsevier Science Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available