Rat H9c2 cardiac myocytes are sensitive to arsenite due to a modest activation of transcription factor Nrf2
Rat H9c2 cardiac myocytes are sensitive to arsenite due to a modest activation of transcription factor Nrf2
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DOI：
10.1007/s00204-011-0700-7
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发表时间：
2011-04
影响因子：
6.1
通讯作者：
D. Sumi;Takahiko Sasaki;H. Miyataka;S. Himeno
中科院分区：
文献类型：
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作者：
D. Sumi;Takahiko Sasaki;H. Miyataka;S. Himeno
砷暴露引起肝毒性的机制已被深入研究。然而，尽管用于治疗急性早幼粒细胞白血病的三氧化二砷会引起心脏毒性，但关于砷诱导心脏毒性的详细机制或与砷剂高度敏感性相关的心脏因素却知之甚少。在这里，我们表明，大鼠H9 c2（2-1）心肌细胞表现出高敏感性无机亚砷酸盐（三价砷）相比，大鼠来源的四个细胞系（肝上皮TRL 1215细胞，肾上皮NRK-52 E细胞，PC 12嗜铬细胞瘤细胞和C6胶质瘤细胞）。此外，我们发现，与TRL 1215细胞相比，H9 c2（2-1）细胞中谷胱甘肽和谷氨酰半胱氨酸连接酶（GCL）的稳态水平较低，导致砷积累增加。此外，我们还检测到As（III）对H9 c2（2-1）细胞GCL和多药耐药相关蛋白（MRP）表达的上调作用较TRL 1215细胞低。已知调节GCL和MRP表达的Nrf 2在保护细胞免受砷污染中起重要作用。我们研究了Nrf 2在H9 c2（2-1）和TRL 1215细胞对砷敏感性差异中的参与，发现Nrf 2在TRL 1215细胞中被As（III）暴露明显激活，但在H9 c2（2-1）细胞中仅被弱激活。综合考虑这些结果，我们提出，在H9 c2（2-1）心肌细胞中暴露于As（III）时，Nrf 2的适度激活会导致砷代谢和排泄能力降低。
The mechanism underlying the hepatotoxicity induced by arsenic exposure is well investigated. However, little is known about the detailed mechanisms of arsenic-induced cardiotoxicity or cardiac factors involved in high sensitivity to arsenicals in spite of the fact that arsenic trioxide, which is used to treat acute promyelocytic leukemia, causes cardiotoxicity. Here, we show that rat H9c2(2-1) cardiac myocytes exhibit high sensitivity to inorganic arsenite (As(III)) as compared with rat-derived four cell lines (liver epithelial TRL1215 cells, kidney epithelial NRK-52E cells, PC12 phechromocytoma cells and C6 glioma cells). Furthermore, we found a lower steady-state level of glutathione and glutamyl-cysteine ligase (GCL) in H9c2(2-1) cells compared with TRL1215 cells, resulting in an increase in arsenic accumulation. In addition, we detected that the up-regulation of GCL and multi-drug resistance-associated protein (MRP) caused by As(III) was extremely low in H9c2(2-1) cells compared with TRL1215 cells. It is known that Nrf2, which regulates GCL and MRP expression, plays an important role in the protection of cells from arsenicals. We investigated the participation of Nrf2 in the difference of sensitivity to arsenicals between H9c2(2-1) and TRL1215 cells and found that Nrf2 was clearly activated by As(III) exposure in TRL1215 cells but only poorly activated in H9c2(2-1) cells. Considering these results together, we propose that modest activation of Nrf2 during exposure to As(III) in H9c2(2-1) cardiac myocytes leads to reduced ability to metabolize and excrete arsenic.