Oxidation of hemoglobin by lipid hydroperoxide associated with low-density lipoprotein (LDL) and increased cytotoxic effect by LDL oxidation in heme oxygenase-1 (HO-1) deficiency
Oxidation of hemoglobin by lipid hydroperoxide associated with low-density lipoprotein (LDL) and increased cytotoxic effect by LDL oxidation in heme oxygenase-1 (HO-1) deficiency
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DOI：
10.1170/t641
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发表时间：
2005-01-01
影响因子：
1.6
通讯作者：
Balla, J
中科院分区：
文献类型：
--
作者：
Nagy, E;Jeney, V;Balla, J
血红素催化氧化低密度脂蛋白（LDL）是参与LDL修饰的相关机制之一。我们之前发现，在人类血红素加氧酶-1（HO-1）缺乏症中，血浆血红蛋白大量氧化为高铁血红蛋白，随后血红素催化的LDL氧化产生对内皮细胞有毒的部分。根据我们以前的观察，我们假设HO-1缺乏儿童的血浆血红蛋白氧化途径涉及LDL相关的脂质过氧化氢。作为支持，LDL相关脂质氢过氧化物以剂量依赖性方式将铁血红蛋白氧化为高铁血红蛋白-已知易于释放其血红素部分。反复血红素暴露的儿童的LDL进一步增加其脂质氢过氧化物含量分钟内导致额外的细胞毒性作用的内皮细胞。氧化LDL的细胞毒性和HO-1诱导能力均强烈依赖于其脂质过氧化氢含量。我们想知道HO-1缺陷患者的细胞是否易于受到血红素介导的LDL氧化引起的氧化损伤。事实上，我们发现血红素催化氧化的低密度脂蛋白在淋巴母细胞衍生的HO-1缺陷的患者引起的细胞毒性升高。我们的结论是，氧化血红蛋白高铁血红蛋白的LDL相关的脂质过氧化氢和增加的HO-1缺陷的儿童细胞的敏感性，氧化LDL的压力可能有助于血管疾病的早期报道。
Heme-catalyzed oxidation of low-density lipoprotein (LDL) is one of the relevant mechanisms involved in LDL modification. We previously revealed a substantial oxidation of plasma hemoglobin to methemoglobin and a subsequent heme-catalyzed LDLoxidation generating moieties toxic to endothelium in heme oxygenase-1 (HO-1)-deficiency in human. Drawing upon our previous observation we posited a pathway for oxidation of plasma hemoglobin in the HO-1-deficient child involving LDL-associated lipid hydroperoxide. In support, LDL-associated lipid hydroperoxide oxidized ferrohemoglobin to methemoglobin - known to readily release its heme moieties - in a dose-dependent manner. Repeated heme exposure of the child's LDL further increased its lipid hydroperoxide content within min leading to additional cytotoxic effect on endothelium. Both cytotoxicity and HO-1 inducing ability of the oxidized LDL were strongly dependent on its lipid hydroperoxide content. We wondered if cells of the HO-1-deficient patient were prone to oxidative damage arising from heme-mediated oxidation of LDL. Indeed, we found elevated cytotoxicity induced by heme-catalyzed oxidation of LDL in lymphoblastoid cells derived from the HO-1-deficient patient. We conclude that oxidation of hemoglobin to methemoglobin by LDL-associated lipid hydroperoxide and increased sensitivity of cells of the HO-1-deficient child to stress of oxidized LDL might contribute to the vascular disorders reported earlier.