Published Online
on May 5, 2003

A more recent version of this article appeared on May 27, 2003

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Submitted on December 9, 2002
Revised on February 24, 2003
Accepted on February 26, 2003

Chronic Iron Administration Increases Vascular Oxidative Stress and Accelerates Arterial Thrombosis

Sharlene M. Day MD^*, Damon Duquaine BS, Lakshmi V. Mundada MS, Rekha G. Menon MD, Bobby V. Khan MD, PhD, Sanjay Rajagopalan MD, and William P. Fay MD

From the University of Michigan Medical School, Division of Cardiology, Ann Arbor (S.M.D., D.D., L.V.M., S.R., W.P.F.); and Emory University School of Medicine, Division of Cardiology, Atlanta, Ga (R.G.M., B.V.K.).

^* To whom correspondence should be addressed. E-mail: sday{at}umich.edu.

Background--Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood.

Methods and Results--We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4±8.5 minutes; n=10) compared with control mice (54.5±35.5 minutes, n=10, P=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of DL-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability.

Conclusions--Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.

Key words: thrombosis • free radicals • arteries

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