Ferritin: a cytoprotective antioxidant strategem of endothelium.
Ferritin: a cytoprotective antioxidant strategem of endothelium.
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DOI：
10.1016/s0021-9258(19)37165-0
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发表时间：
1992-09
期刊：
影响因子：
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通讯作者：
G. Balla;H. Jacob;J. Balla;M. Rosenberg;K. Nath;F. Apple;J. Eaton;G. Vercellotti
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文献类型：
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作者：
G. Balla;H. Jacob;J. Balla;M. Rosenberg;K. Nath;F. Apple;J. Eaton;G. Vercellotti
吞噬细胞介导的血管内皮氧化损伤可能涉及多种血管病变，包括动脉粥样硬化和肺泄漏综合征，如成人呼吸窘迫综合征。我们已经证明血红素，一种疏水铁螯合物，在内皮细胞中迅速结合，在短短1小时后，它显着加重了由多形核白细胞氧化剂或过氧化氢（H2O2）引起的细胞毒性。然而，相反，如果用血红素短暂脉冲培养内皮细胞，然后让其长时间孵育（16小时），细胞对氧化介导的损伤和内皮脂质过氧化产物的积累具有高度的抵抗力。这种保护作用与4小时内血红素加氧酶和铁蛋白mrna的诱导有关。16 h后，血红素加氧酶和铁蛋白分别增加了约50倍和10倍。这些蛋白的差异诱导决定了铁蛋白可能是最终的细胞保护剂。铁蛋白抑制氧化介导的细胞溶解与其细胞内浓度直接相关。当添加到培养的内皮细胞中时，载铁蛋白以剂量反应的方式被吸收，并通过免疫荧光显示为细胞质颗粒；以类似的剂量反应方式，添加的载铁蛋白保护内皮细胞免受氧化介导的细胞溶解。相反，位点导向的铁蛋白突变体（重链Glu62—Lys； His65—Gly）缺乏铁氧化酶活性，缺乏铁隔离能力，完全不能作为细胞保护剂。我们得出结论，内皮细胞和其他类型的细胞可能通过铁螯合剂铁蛋白免受氧化损伤。
Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62—-Lys; His65—-Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.