Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin: implications for the design of hemoglobin-based oxygen carriers
Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin: implications for the design of hemoglobin-based oxygen carriers
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DOI：
10.1042/bsr20180370
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发表时间：
2018-08-31
影响因子：
4
通讯作者：
Cooper, Chris E.
中科院分区：
文献类型：
--
作者：
Simons, Michelle;Gretton, Svetlana;Cooper, Chris E.
基于血红蛋白（Hb）的氧载体（HBOC）已被工程化以替代或增加红细胞的携氧能力。然而，临床结果通常是令人失望的，部分原因是由于Hb的内在氧化毒性。最常见的HBOC起始材料是成人或牛Hb。然而，有人认为，胎儿血红蛋白可能提供的优势，由于降低氧化反应性。HBOC的大规模生产将可能并最终需要人类蛋白质的重组来源。因此，我们直接比较了重组胎儿（rHbF）和重组成人（rHbA）Hb的功能特性和氧化反应性。rHbA和rHbF产生类似的纯化功能蛋白的产量。两种蛋白质的自氧化速率、过氧化氢反应速率、NO清除双加氧酶活性和NO产生亚硝酸还原酶活性无差异。rHbF蛋白为：低水平的过氧化氢损伤较小;当以铁形式加入人脐静脉内皮细胞（HUVEC）时损伤较小;并且具有较慢的内在血红素损失速率。rHbA蛋白为：更容易被血浆抗氧化剂如活性铁基和三价铁状态的抗坏血酸还原;更不容易被脂质过氧化物破坏;和对磷脂酰胆碱脂质体的破坏更小。总之，在氧化反应性方面，使用rHbA或rHbF作为有效HBOC的基础有优点和缺点。
Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested that fetal Hb may offer advantages due to decreased oxidative reactivity. Large-scale manufacturing of HBOC will likely and ultimately require recombinant sources of human proteins. We, therefore, directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) Hb. rHbA and rHbF produced similar yields of purified functional protein. No differences were seen in the two proteins in: autoxidation rate; the rate of hydrogen peroxide reaction; NO scavenging dioxygenase activity; and the NO producing nitrite reductase activity. The rHbF protein was: less damaged by low levels of hydrogen peroxide; less damaging when added to human umbilical vein endothelial cells (HUVEC) in the ferric form; and had a slower rate of intrinsic heme loss. The rHbA protein was: more readily reducible by plasma antioxidants such as ascorbate in both the reactive ferryl and ferric states; less readily damaged by lipid peroxides; and less damaging to phosphatidylcholine liposomes. In conclusion in terms of oxidative reactivity, there are advantages and disadvantages to the use of rHbA or rHbF as the basis for an effective HBOC.