Ferriporphyrins and endothelium: a 2-edged sword - promotion of oxidation and induction of cytoprotectants
Ferriporphyrins and endothelium: a 2-edged sword - promotion of oxidation and induction of cytoprotectants
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DOI：
10.1182/blood.v95.11.3442.011k51_3442_3450
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发表时间：
2000-06-01
期刊：
影响因子：
20.3
通讯作者：
Vercellotti, GM
中科院分区：
文献类型：
--
作者：
Balla, J;Balla, G;Vercellotti, GM
血红素精氨酸输注可减轻急性间歇性卟啉症患者的症状，但未见血红素的血管或血栓副作用的报道，为了为血红素精氨酸的安全性提供理论依据，本研究观察了不同铁卟啉对内皮细胞自由基损伤的敏感性以及诱导血红素加氧酶和铁蛋白表达的效果。与血红素不同，血红素精氨酸不能放大过氧化氢(5.3+/-2.4比62.3+/-5.3%铬-51释放，P<；0.0001)或激活的中性粒细胞(14.4+/-2.9比41.1+/-6.0%，P<；0.0001)所介导的氧化剂诱导的细胞毒性，然而，与血红素一样，血红素精氨酸也能有效地进入内皮细胞，因为两者都能显著诱导血红素加氧酶mRNA(增加20倍以上)和酶活性。即使有有效的渗透，与血红素诱导的10倍相比，内皮细胞铁蛋白的含量只有很小的增加；推测尽管血红素加氧酶上调，但从血红素精氨酸中获得的游离铁较少，由于其显著催化低密度脂蛋白(LDL)氧化为内皮毒性部分，血红素可能是血管病变，血红素精氨酸的催化作用显著减弱。血红素精氨酸处理的低密度脂蛋白对血管内皮细胞的毒性不到血红素处理的低密度脂蛋白的一半(P<；0.004)。结论是，血红素精氨酸对血管的毒性可能比血红素小，因为它是一种有效的血红素加氧酶基因调节剂，但不是一种效率较低的自由基催化剂。(C)2000年，由美国血液病学会提供。
Heme arginate infusions blunt the symptoms of patients with acute intermittent porphyria without evidence of the vascular or thrombotic side effects reported for hematin, To provide a rationale for heme arginate's safety, the present study examined the effects of various ferriporphyrins to sensitize human endothelial cells to free radical injury and to induce heme oxygenase and ferritin expression. Heme arginate, unlike hematin, did not amplify oxidant-induced cytotoxicity mediated by hydrogen peroxide (5.3 +/- 2.4 versus 62.3 +/- 5.3% Cr-51 release, P < .0001) or by activated neutrophils (14.4 +/- 2.9 versus 41.1 +/- 6.0%, P < .0001), Nevertheless, heme arginate efficiently entered endothelial cells similarly to hematin, since both markedly induced heme oxygenase mRNA (more than 20-fold increase) and enzyme activity. Even with efficient permeation, endothelial cell ferritin content was only minimally increased by heme arginate compared with a 10-fold induction by hematin; presumably less free iron was derived from heme arginate despite up-regulation of heme oxygenase, Hematin is potentially vasculopathic by its marked catalysis of oxidation of low-density lipoprotein (LDL) to endothelial-toxic moieties, Heme arginate was significantly less catalytic. Heme arginate-conditioned LDL was less than half as cytotoxic to endothelial cells as hematin-conditioned LDL (P < .004), It is concluded that heme arginate may be less vasculotoxic than hematin since it is an effective heme oxygenase gene regulator but a less efficient free radical catalyst. (C) 2000 by The American Society of Hematology.