Chronic iron overload in rats increases vascular reactivity by increasing oxidative stress and reducing nitric oxide bioavailability.

AIMS: Iron overload in animal models and humans increases oxidative stress and induces cardiomyopathy. It has been suggested that the vasculature is also damaged, but the impacts on vascular reactivity and the underlying mechanisms remain poorly understood. In this study, we aimed to identify possible changes in the vascular reactivity of aortas from iron overloaded rats and investigate the underlying mechanisms.

MAIN

METHODS

Rats were treated with 100mg/kg/day iron-dextran, ip, five days a week for four weeks and compared to a saline-injected group.

KEY FINDINGS: Chronic iron administration increased serum iron and transferrin saturation with significant deposition in the liver. Additionally, iron overload significantly increased the vasoconstrictor response in aortic rings as assessed in vitro, with reduced influence of endothelial denudation or l-NAME incubation on the vascular reactivity. In vitro assay with DAF-2 indicated reduced NO production in the iron overload group. Iron overload-induced vascular hyperactivity was reversed by incubation with tiron, catalase, apocynin, allopurinol and losartan. Moreover, malondialdehyde was elevated in the plasma, and O2(•-) generation and NADPH oxidase subunit (p22phox) expression were increased in the aortas of iron-loaded rats.

SIGNIFICANCE: Our results demonstrated that chronic iron overload is associated with altered vascular reactivity and the loss of endothelial modulation of the vascular tone. This iron loading-induced endothelial dysfunction and reduced nitric oxide bioavailability may be a result of increased production of reactive oxygen species and local renin-angiotensin system activation.