Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis
Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis
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DOI：
10.1161/01.cir.0000066910.02844.d0
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发表时间：
2003-05-27
期刊：
影响因子：
37.8
通讯作者：
Fay, WP
中科院分区：
文献类型：
--
作者：
Day, SM;Duquaine, D;Fay, WP
背景——铁超负荷与缺血性心血管事件的发病机制有关。然而，铁过量对血管功能以及对血管损伤的血栓形成反应的影响尚不清楚。方法和结果——我们研究了长期服用右旋糖酐铁（6周内15毫克）对小鼠血栓形成、全身和血管氧化应激以及内皮依赖性血管反应性的影响。与对照小鼠（54.5±35.5 分钟，n=10，P=0.009）相比，铁负荷小鼠光化学颈动脉损伤后血栓形成加速（闭塞血栓形成的平均时间，20.4±8.5 分钟；n=10）。铁负荷对血浆凝固、血管壁组织因子活性或 ADP 诱导的血小板聚集没有影响。急性施用dl-半胱氨酸（一种活性氧清除剂）完全消除了铁负荷对血栓形成的影响，表明铁通过促氧化机制加速血栓形成。铁负荷增强了全身和血管活性氧的产生。在铁负荷小鼠中，内皮依赖性血管舒张功能受损，表明一氧化氮生物利用度降低。结论——中等铁负荷显着加速动脉损伤后血栓形成，增加血管氧化应激，并损害血管反应性。铁引起的血管功能障碍可能导致与慢性铁超负荷相关的缺血性心血管事件的发生率增加。
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 ofdl-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.