Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages - Activation by oxidatively modified LDL and 4-hydroxynonenal
Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages - Activation by oxidatively modified LDL and 4-hydroxynonenal
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DOI：
10.1161/01.res.0000119171.44657.45
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发表时间：
2004-03-19
影响因子：
20.1
通讯作者：
Mann, GE
中科院分区：
文献类型：
--
作者：
Ishii, T;Itoh, K;Mann, GE
CD 36是介导氧化低密度脂蛋白（oxLDL）摄取的重要清道夫受体，在泡沫细胞形成和动脉粥样硬化的发病机制中起关键作用。我们报告的第一个证据表明，转录因子Nrf 2在血管平滑肌细胞中表达，并证明oxLDL导致Nrf 2在小鼠巨噬细胞的核积累，导致编码CD 36和应激蛋白A170，血红素加氧酶-1（HO- 1）和过氧化物酶I（Prx I）的基因的激活。4-羟基-2-壬烯醛（HNE），来自脂质过氧化反应，是Nrf 2最有效的激活剂之一。使用Nrf 2缺陷型巨噬细胞，我们确定Nrf 2部分调节CD 36表达以响应oxLDL、HNE或亲电子试剂马来酸二乙酯。在鼠主动脉平滑肌细胞中，表达可忽略不计的水平的CD 36，中度和高度氧化的LDL只引起有限的Nrf 2易位和可忽略不计的增加A170，HO- 1，和Prx I的表达。然而，用HNE处理平滑肌细胞显著增强了Nrf 2的核积聚，并增加了A170、HO- 1和Prx I蛋白水平。由于PPAR-gamma可以被oxLDL激活并控制巨噬细胞中CD 36的表达，我们的研究结果表明Nrf 2是第二个重要的转录因子，参与了动脉粥样硬化中清道夫受体CD 36和抗氧化应激基因的诱导。
CD36 is an important scavenger receptor mediating uptake of oxidized low- density lipoproteins ( oxLDLs) and plays a key role in foam cell formation and the pathogenesis of atherosclerosis. We report the first evidence that the transcription factor Nrf2 is expressed in vascular smooth muscle cells, and demonstrate that oxLDLs cause nuclear accumulation of Nrf2 in murine macrophages, resulting in the activation of genes encoding CD36 and the stress proteins A170, heme oxygenase- 1 ( HO- 1), and peroxiredoxin I ( Prx I). 4- Hydroxy- 2- nonenal ( HNE), derived from lipid peroxidation, was one of the most effective activators of Nrf2. Using Nrf2- deficient macrophages, we established that Nrf2 partially regulates CD36 expression in response to oxLDLs, HNE, or the electrophilic agent diethylmaleate. In murine aortic smooth muscle cells, expressing negligible levels of CD36, both moderately and highly oxidized LDL caused only limited Nrf2 translocation and negligible increases in A170, HO- 1, and Prx I expression. However, treatment of smooth muscle cells with HNE significantly enhanced nuclear accumulation of Nrf2 and increased A170, HO- 1, and Prx I protein levels. Because PPAR-gamma can be activated by oxLDLs and controls expression of CD36 in macrophages, our results implicate Nrf2 as a second important transcription factor involved in the induction of the scavenger receptor CD36 and antioxidant stress genes in atherosclerosis.