Oxidized Mutant Human Hemoglobins S and E Induce Oxidative Stress and Bioenergetic Dysfunction in Human Pulmonary Endothelial Cells.
Oxidized Mutant Human Hemoglobins S and E Induce Oxidative Stress and Bioenergetic Dysfunction in Human Pulmonary Endothelial Cells.
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DOI：
10.3389/fphys.2017.01082
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发表时间：
2017
影响因子：
4
通讯作者：
Alayash AI
中科院分区：
文献类型：
--
作者：
Jana S;Meng F;Hirsch RE;Friedman JM;Alayash AI
在镰状细胞病 (SCD) 或地中海贫血的溶血发作期间，无细胞血红蛋白 (Hb) 在循环中被氧化，并可能导致损害血管系统的严重并发症。溶血性贫血通常与肺动脉高压（PH）相关，并且通常是由肺内皮细胞功能障碍引起的。本研究的目的是确定不同 Hb 对培养的人肺内皮功能的影响。为了实现这一目标，在与成人 Hb (HbA) 以及从镰状细胞 Hb (HbS、βV6E) 和 HbE (βE26K) 患者分离的 Hb 孵育后，对培养的人肺动脉内皮细胞 (HPAEC) 中的内皮通透性、氧化应激反应参数、糖酵解和线粒体生物能功能进行监测。 与β-地中海贫血并存。这些突变型血红蛋白以其独特的氧化特征而闻名。用亚铁形式的 HbE、HbS 处理 24 小时，表现出内皮单层完整性的更高程度的损失，同时活性氧自由基的产生、脂质过氧化氢的形成和氧化应激反应蛋白（包括血红素加氧酶-1 (HO-1)）的表达增加，并伴随着解偶联线粒体呼吸的增加。触珠蛋白（Hp，蛋白质清除剂）、血红素结合蛋白（Hpx，血红素清除剂）或抗坏血酸（还原剂）部分减少了膜通透性的损失。为了了解 Hb 氧化的作用，将 HPAEC 暴露于突变型 Hb 的铁态或铁态。所有蛋白质的铁基形式对内皮单层完整性的损害程度均高于其各自的铁血红蛋白。 HbS 和 HbE 的铁基形式还导致分离的内皮线粒体中呼吸链复合物活性的丧失以及 HPAEC 中基础耗氧量的丧失。然而，与ferry1 Hbs一起孵育更长时间会产生生物能重编程，包括更高程度的解偶联呼吸和糖酵解速率。本报告中的数据共同表明，HbS 和 HbE 的较高氧化形式通过涉及线粒体生物能功能的不同损伤机制导致内皮功能障碍。
Cell free hemoglobin (Hb), becomes oxidized in the circulation during hemolytic episodes in sickle cell disease (SCD) or thalassemia and may potentially cause major complications that are damaging to the vascular system. Hemolytic anemias are commonly associated with pulmonary hypertension (PH) and often result from dysfunction of lung endothelial cells. The aim of this study was to determine the effect of different Hbs on cultured human lung endothelial function. Toward this goal, endothelial permeability, oxidative stress response parameters, glycolytic and mitochondrial bioenergetic functions were monitored in cultured human pulmonary arterial endothelial cells (HPAEC) following incubation with human adult Hb (HbA), and Hb isolated from patients with sickle cell Hb (HbS, βV6E) and HbE (βE26K) that commonly co-exist with β-thalassemia. These mutant Hbs are known for their distinct oxidative profiles. HPAEC treated with the ferrous forms of HbE, HbS for 24 h showed higher loss of endothelial monolayer integrity with concomitant rise in reactive oxygen radical production, lipid hydroperoxide formation and higher expressions of oxidative stress response proteins including heme oxygenase-1 (HO-1) accompanied by a rise in uncoupled mitochondrial respiration. Loss of membrane permeability was diminished in part by haptoglobin (Hp, protein scavenger), hemopexin (Hpx, heme scavenger) or ascorbate (reducing agent). To understand the role of Hb oxidation, HPAEC were exposed to ferric or ferryl states of the mutant Hbs. Ferryl forms of all proteins caused a significant damage to the endothelial monolayer integrity at a higher degree than their respective ferric Hbs. Ferryl forms of HbS and HbE also caused a loss of respiratory chain complex activities in isolated endothelial mitochondria and basal oxygen consumption in HPAEC. However, longer incubation with ferryl Hbs produced bioenergetic reprogramming including higher degree of uncoupled respiration and glycolytic rate. The data in this report collectively indicate that higher oxidation forms of HbS and HbE cause endothelial dysfunction through distinct damaging mechanisms involving mitochondrial bioenergetic function.
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影响因子：
7.4
作者：
Chiu, DTY;VanDenBerg, J;Liu, TZ
通讯作者：
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影响因子：
4.1
作者：
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影响因子：
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作者：
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影响因子：
2.3
作者：
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Hirsch, Rhoda Elison
DOI：
10.1016/j.bbadis.2011.02.013
发表时间：
2011-06-01
影响因子：
6.2
作者：
Jana, Sirsendu;Sinha, Maitrayee;Chakrabarti, Sasanka
通讯作者：
Chakrabarti, Sasanka