Haem, haem oxygenase and ferritin in vascular endothelial cell injury.
Haem, haem oxygenase and ferritin in vascular endothelial cell injury.
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DOI：
10.1093/ndt/gfg1034
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发表时间：
2003-07-01
影响因子：
6.1
通讯作者：
Balla, Gyorgy
中科院分区：
文献类型：
--
作者：
Balla, Jozsef;Vercellotti, Gregory A.;Balla, Gyorgy
铁源性活性氧（ROS）与许多血管疾病的发病机制有关，包括动脉粥样硬化、微血管病溶血性贫血、血管炎和再灌注损伤。血红素是氧化还原活性铁的一个丰富来源，当从细胞内血红素蛋白中释放出来时，它本身就是危险的。本综述关注血红素在血管内皮细胞损伤中的可能参与以及内皮细胞减少这种损伤的策略。内皮细胞暴露于血红素大大增强了由多形核白细胞和其他ROS来源介导的细胞杀伤。游离血红素也促进低密度脂蛋白转化为细胞毒性氧化产物。如果仅仅因为它的丰度，血红蛋白可能是血管内皮内血红素最重要的潜在来源；血浆中的游离血红蛋白被氧化后，可将血红素转移到内皮，从而增强细胞对氧化介导的损伤的敏感性。作为对这种毒性的防御，暴露于游离血红素后，内皮细胞上调血红素氧化酶-1和铁蛋白。血红素加氧酶是一种血红素降解酶，它能打开卟啉环，产生胆绿素、一氧化碳和一种最危险的产物——无氧化活性铁。铁蛋白是一种多聚体蛋白，具有非常高的储存铁的能力。这些体内平衡调节已被证明是有效的保护内皮对抗外源性血红素和氧化剂的破坏作用。最近，一名儿童被诊断为血红素氧化酶-1缺乏症，表现出广泛的内皮损伤，这一保护系统的核心重要性得到了强调。
Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product-free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.