Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury
Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury
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DOI：
10.1074/jbc.m404800200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Ho, DS
中科院分区：
文献类型：
--
作者：
Ho, YS;Xiong, Y;Ho, DS
过氧化氢酶通过分解过氧化氢，从而防止由芬顿反应产生羟基自由基，在细胞抗氧化防御中起主要作用。在无催化酶血症和低催化酶血症小鼠中，过氧化氢酶缺乏的程度因组织而异。因此，它们可能不适合研究这种酶在某些氧化剂介导的组织损伤模型中的功能。我们试图通过基因打靶技术产生一种新的过氧化氢酶缺失小鼠品系。通过用新霉素抗性盒替换内含子4和外显子5的部分来破坏小鼠过氧化氢酶（Cat或Cas1）基因。完全缺乏过氧化氢酶表达的纯合子Cat基因敲除小鼠发育正常，没有显示出明显异常。与野生型小鼠相比，敲除小鼠的肝、肺和晶状体切片在分解细胞外过氧化氢方面表现出延迟速率。然而，过氧化氢酶缺乏的小鼠并不更容易受到高氧诱导的肺损伤，他们的晶状体也没有表现出任何增加的敏感性，由光化学反应产生的氧化应激，这表明过氧化氢酶的抗氧化功能在这两种模型的氧化损伤是可以忽略不计的。进一步的研究表明，物理冲击造成的皮质损伤导致Cat基因敲除小鼠脑线粒体中NAD相关的电子转移活性和能量耦合能力显著降低，但野生型小鼠没有。观察到的线粒体呼吸效率降低可能是线粒体相关钙增加的直接结果，这是继发于氧化应激增加的。这些研究表明，过氧化氢酶在抗氧化防御中的作用取决于组织类型和氧化剂介导的组织损伤模型。
Catalase plays a major role in cellular antioxidant defense by decomposing hydrogen peroxide, thereby preventing the generation of hydroxyl radical by the Fenton reaction. The degree of catalase deficiency in acatalasemic and hypocatalasemic mice varies from tissue to tissue. They therefore may not be suitable for studying the function of this enzyme in certain models of oxidant-mediated tissue injury. We sought to generate a new line of catalase null mice by the gene targeting technique. The mouse catalase (Cat or Cas1) gene was disrupted by replacing parts of intron 4 and exon 5 with a neomycin resistance cassette. Homozygous Cat knockout mice, which are completely deficient in catalase expression, develop normally and show no gross abnormalities. Slices of liver and lung and lenses from the knockout mice exhibited a retarded rate in decomposing extracellular hydrogen peroxide compared with those of wild-type mice. However, mice deficient in catalase were not more vulnerable to hyperoxia-induced lung injury; nor did their lenses show any increased susceptibility to oxidative stress generated by photochemical reaction, suggesting that the antioxidant function of catalase in these two models of oxidant injury is negligible. Further studies showed that cortical injury from physical impact caused a significant decrease in NAD-linked electron transfer activities and energy coupling capacities in brain mitochondria of Cat knockout mice but not wild-type mice. The observed decrease in efficiency of mitochondrial respiration may be a direct result of an increase in mitochondrion-associated calcium, which is secondary to the increased oxidative stress. These studies suggest that the role of catalase in antioxidant defense is dependent on the type of tissue and the model of oxidant-mediated tissue injury.