Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function
Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function
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DOI：
10.1128/mcb.24.21.9414-9423.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Brielmeier, M
中科院分区：
文献类型：
--
作者：
Conrad, M;Jakupoglu, C;Brielmeier, M
氧自由基调节信号、增殖和细胞凋亡等多种生理过程，在病理生理和疾病发展中起着关键作用。至少有两个硫氧还蛋白还原酶/硫氧还蛋白/过氧化还蛋白系统参与细胞对氧自由基的防御。目前，人们对不同类型细胞中单个酶对氧化还原代谢的贡献知之甚少。为了开始解决这个问题，我们培育了缺乏功能性线粒体硫氧还蛋白还原酶(TrxR2)的小鼠，并对其进行了鉴定。普遍存在的Cre介导的TrxR2失活与胚胎第13天的胚胎死亡有关。TrxR2(-/-)胚胎较小，严重贫血，并显示肝脏细胞凋亡增加。体外培养的造血祖细胞集落的大小显著减少。当谷胱甘肽合成受到抑制时，TrxR2缺陷的胚胎成纤维细胞对内源性氧自由基高度敏感。TrxR2(-/-)胚胎除造血功能障碍外，其室壁变薄，心肌细胞增殖减少。限制心脏组织消融TrxR2导致致命的扩张型心肌病，这种情况使人想起克山病和Friedreich‘s共济失调。我们得出结论，TrxR2在造血和心脏功能中都起着关键作用。
Oxygen radicals regulate many physiological processes, such as signaling, proliferation, and apoptosis, and thus play a pivotal role in pathophysiology and disease development. There are at least two thioredoxin reductase/ thioredoxin/peroxiredoxin systems participating in the cellular defense against oxygen radicals. At present, relatively little is known about the contribution of individual enzymes to the redox metabolism in different cell types. To begin to address this question, we generated and characterized mice lacking functional mitochondrial thioredoxin reductase (TrxR2). Ubiquitous Cre-mediated inactivation of TrxR2 is associated with embryonic death at embryonic day 13. TrxR2(-/-) embryos are smaller and severely anemic and show increased apoptosis in the liver. The size of hematopoietic colonies cultured ex vivo is dramatically reduced. TrxR2-deficient embryonic fibroblasts are highly sensitive to endogenous oxygen radicals when glutathione synthesis is inhibited. Besides the defect in hematopoiesis, the ventricular heart wall of TrxR2(-/-) embryos is thinned and proliferation of cardiomyocytes is decreased. Cardiac tissue-restricted ablation of TrxR2 results in fatal dilated cardiomyopathy, a condition reminiscent of that in Keshan disease and Friedreich's ataxia. We conclude that TrxR2 plays a pivotal role in both hematopoiesis and heart function.