Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation
Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation
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DOI：
10.1016/j.freeradbiomed.2012.10.001
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发表时间：
2012-12-15
影响因子：
7.4
通讯作者：
Itoh, Ken
中科院分区：
文献类型：
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作者：
Harada, Nobuhiko;Ito, Koichi;Itoh, Ken
动脉粥样硬化是心肌梗死和脑卒中的主要病因，迫切需要预防动脉粥样硬化的策略。在动脉粥样硬化的情况下，据报道，Nrf2基因的缺失可以减轻动脉粥样硬化的形成。Nrf2基因编码哺乳动物氧化应激反应的主要调节因子。然而，预防动脉粥样硬化的确切机制在很大程度上是未知的。为了进一步阐明Nrf2在体内动脉粥样硬化中的作用，我们利用ApoE敲除（KO）小鼠模型对动脉粥样硬化的发展进行了时间过程分析。结果表明，在HFC（高脂高胆固醇）饮食开始后5周，油红o染色的病变大小相似，但与ApoE KO小鼠（A0N2小鼠）相比，Nrf2和ApoE双KO小鼠（A0N0小鼠）的病变在12周时明显减弱。与这些结果一致的是，免疫组织化学分析显示Nrf2激活在晚期动脉粥样硬化斑块中观察到，而在早期病变中没有。对12周动脉粥样硬化斑块的RT-qPCR分析显示，与A0N2小鼠相比，A0N0小鼠中Nrf2靶基因Ho-1和SLPI的表达水平明显降低，这种变化与A0N0小鼠巨噬细胞m1亚型基因精氨酸酶II和诱导型NO合成酶的表达降低有关。此外，骨髓移植（BMT）分析显示，骨髓来源细胞中的Nrf2活性有助于病变的形成。因此，我们的研究表征了Nrf2在动脉粥样硬化发生过程中对脑梗死源性细胞的积极作用，这表明Nrf2可能影响斑块的炎症反应。(C) 2012爱思唯尔公司版权所有。
Atherosclerosis is the major etiology underlying myocardial infarction and stroke, and strategies for preventing atherosclerosis are urgently needed. In the context of atherosclerosis, the deletion of the Nrf2 gene, which encodes a master regulator of the oxidative stress response in mammals, reportedly attenuates atherosclerosis formation. However, the precise mechanisms of protection against atherosclerosis are largely unknown. To further clarify the role of Nrf2 in atherosclerosis in vivo, we performed a time course analysis of atherosclerosis development utilizing an ApoE knockout (KO) mouse model. The results demonstrate that oil red O-stainable lesions were similar in size 5 weeks after the initiation of an HFC (high fat and high cholesterol) diet, but the lesions were markedly attenuated in the Nrf2 and ApoE double KO mice (A0N0 mice) compared with the lesions in the ApoE KO mice (A0N2 mice) at 12 weeks. Consistent with these results, the immunohistochemical analysis revealed that Nrf2 activation is observed in late-stage atherosclerotic plaques but not in earlier lesions. The RT-qPCR analysis of 12-week atherosclerotic plaques revealed that Nrf2 target genes, such as Ho-1 and SLPI, are expressed at significantly lower levels in the A0N0 mice compared with the A0N2 mice, and this change was associated with a decreased expression Of macrophage M1-subtype genes Arginase II and inducible NO synthase in the A0N0 Mice. furthermore, the bone marrow (BM) transplantation (BMT) analysis revealed that the Nrf2 activity in the BM-derived cells contributed to lesion formation. Therefore, our study has characterized the positive role of Nrf2 in the BM-derived cells during the development of atherosclerosis, which suggest that Nrf2 may influence the inflammatory reactions in the plagues. (C) 2012 Elsevier Inc. All rights reserved.