A transgenic mouse model expressing exclusively human hemoglobin E: Indications of a mild oxidative stress
A transgenic mouse model expressing exclusively human hemoglobin E: Indications of a mild oxidative stress
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DOI：
10.1016/j.bcmd.2011.12.002
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发表时间：
2012-02-15
影响因子：
2.3
通讯作者：
Hirsch, Rhoda Elison
中科院分区：
文献类型：
--
作者：
Chen, Qiuying;Fabry, Mary E.;Hirsch, Rhoda Elison
血红蛋白（Hb）E（β 26 Glu -> Lys）是世界上最常见的异常血红蛋白（Hb）变体。由于交替剪接突变，HbE纯合子为轻度地中海贫血，并表现为良性临床表现（小红细胞和轻度贫血），伴有罕见临床症状。鉴于人红细胞（RBC）含有HbE和过量的α-链沿着少量血红蛋白，单独HbE对RBC病理生理学的影响尚未阐明。这对于高度病态的β（E）-地中海贫血疾病变得至关重要。我们已经产生了专门表达人HbE（HbEKO）的转基因小鼠，其表现出已知的β（E）珠蛋白mRNA的异常剪接，但基本上是非地中海贫血的，如RBC α/β（人）珠蛋白链合成所证明的。这些小鼠表现出与人类EE个体相似的血液学特征：MCV和MCH低但MCHC正常的小红细胞RBC;目标RBC;轻度贫血伴Hb、HCT低和网织红细胞水平轻度升高以及渗透脆性降低，表明RBC表面积与体积比改变。这些变化与轻度RBC氧化应激相关，表现为膜脂质过氧化作用增强、锌原卟啉水平升高以及心脏功能发生微小但显著的变化。将在HbS或HbA存在下表达HbE的C57（背景）小鼠和完全KO小鼠模型用作对照。在选择的情况下，比较HbA完全KO小鼠模型，但发现由于其RBC地中海贫血特征而受到限制。由于HbEKO小鼠RBC缺乏近似于小鼠地中海贫血（或人地中海贫血）的过量α-链的丰度，结果表明观察到的体内RBC轻度氧化应激至少部分地由HbE突变的分子后果引起。(C)2011 Elsevier Inc. All rights reserved.
Hemoglobin (Hb) E (beta 26 Glu -> Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess alpha-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid beta(E)-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of beta(E) globin mRNA, but are essentially non-thalassemic as demonstrated by RBC alpha/beta (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess alpha-chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation. (C) 2011 Elsevier Inc. All rights reserved.