Iron as a Novel Risk Factor for Endothelial Dysfunction in Humans

Abstract

P130 Iron is a transition metal which generates reactive oxygen species (ROS). ROS-induced oxidative stress impairs endothelial function and plays a central role in the pathogenesis of atherosclerosis. To investigate whether body iron store is associated with endothelial dysfunction via oxidative stress, the effects of 1) parenteral iron loading and 2) iron chelation on endothelial function were measured. 1) In healthy volunteers, we administrated therapeutic dose of iron dextran (0.7 mg/kg body weight, i.v.) or vehicle, and examined flow-mediated vasodilation (FMD) of the brachial artery by high resolution ultrasonography, as a non-invasive measure of endothelial function. We also measured plasma levels of malondialdehyde (MDA), as an index of oxidative stress. Iron loading increased plasma levels of iron (from 89±13 to 232±12 mg/dl, p<.0001) and decreased FMD (from 9.2±1.4 to 5.3±1.1 %, p<.0003). Plasma levels of MDA were significantly increased after iron loading (from 2.4±0.2 to 3.1±0.2 nmol/ml, p<.0005) and were positively correlated with plasma iron concentrations (r=.64, p<.005). 2) In smokers without apparent cardiovascular disease, we administrated an iron chelator, deferoxamine (8.3 mg/kg body weight, i.v.) or vehicle, and measured FMD and MDA. Iron chelation by deferoxamine eliminated plasma iron (from 105±16 to 88±11 mg/dl, p<.02) and restored FMD in smokers (from 4.6±0.4 to 7.7±0.7 %, p<.0008), whereas plasma MDA was significantly decreased after deferoxamine (from 2.5±0.2 to 2.2±0.2 nmol/ml, p<.01). In each experiment, vehicle had no effects on vascular function or MDA and endothelium-independent vasodilation by nitroglycerin was not changed. Thus, iron loading exacerbated and iron chelation restored endothelial function paralleled with lipid peroxidation. Our series of experiments suggest that increased body iron stores may be associated with cardiovascular events via ROS-related endothelial dysfunction.