Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice
Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice
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DOI：
10.1111/j.1365-2443.2006.00979.x
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发表时间：
2006-07-01
期刊：
影响因子：
2.1
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Yano, Yoko;Ozono, Ryoji;Igarashi, Kazuhiko
Bach 1是血红素加氧酶-1基因（Hmox-1）和β-珠蛋白基因的转录抑制因子。血红素加氧酶（HO）-1是一种诱导型细胞保护酶，其将促氧化剂血红素降解为一氧化碳（CO）和胆绿素/胆红素，其被认为介导HO-1的抗炎和抗氧化作用。在本研究中，我们研究了Bach 1在体内心肌缺血/再灌注（I/R）损伤的组织保护作用，使用缺乏Bach 1基因的小鼠（Bach 1（-/-））和野生型（Bach 1（+/+））小鼠。在Bach 1（-/-）小鼠中，心肌HO-1蛋白的表达与Bach 1（+/+）小鼠相比组成性上调3.4倍。虽然心肌I/R诱导HO-1蛋白在缺血心肌细胞在两个品系的小鼠，诱导的程度显着大于Bach 1（+/+）小鼠Bach 1（-/-）。Bach 1（-/-）小鼠的心肌梗死面积显着减少了48.4%。用锌原卟啉（HO活性抑制剂）预处理Bach 1（-/-）小鼠，可消除Bach 1破坏的梗死减少作用，表明梗死面积的减少至少部分由HO-1活性介导。因此，Bach 1在心肌中HO-1的组成型和诱导型表达水平的设定中起着关键作用。在I/R过程中Bach 1失活似乎是控制HO-1参与的细胞保护程序激活水平的关键机制。
Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and beta-globin gene. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades pro-oxidant heme to carbon monoxide (CO) and biliverdin/bilirubin, which are thought to mediate anti-inflammatory and anti-oxidant actions of HO-1. In the present study, we investigated the role of Bach1 in tissue protection against myocardial ischemia/reperfusion (I/R) injury in vivo using mice lacking the Bach1 gene (Bach1(-/-)) and wild-type (Bach1(+/+)) mice. In Bach1(-/-) mice, myocardial expression of HO-1 protein was constitutively up-regulated by 3.4-fold compared to that in Bach1(+/+) mice. While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1(-/-) mice than in Bach1(+/+) mice. Myocardial infarction was markedly reduced in size by 48.4% in Bach1(-/-) mice. Pretreatment of Bach1(-/-) mice with zinc-protoporphyrin, an inhibitor of HO activity, abolished the infarction-reducing effect of Bach1 disruption, indicating that reduction in the infarct size was mediated, at least in part, by HO-1 activity. Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium. Bach1 inactivation during I/R appears to be a key mechanism controlling the activation level of cytoprotective program involving HO-1.