Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis.
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.


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.
University of Michigan Medical School, Division of Cardiology, Ann Arbor, USA. sday@umich.edu
Sharlene M
SM
Day
Damon
D
Duquaine
Lakshmi V
LV
Mundada
Rekha G
RG
Menon
Bobby V
BV
Khan
Sanjay
S
Rajagopalan
William P
WP
Fay
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002341:Carotid Artery Thrombosis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D003545:Cysteine / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007501:Iron / Q000633:toxicity*; D019190:Iron Overload / Q000139:chemically induced* / Q000503:physiopathology; D007505:Iron-Dextran Complex / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013995:Time; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D007505:Iron-Dextran Complex; D013925:Thromboplastin; D007501:Iron; D003545:Cysteine