Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism
Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism
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DOI：
10.1155/2018/6209110
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发表时间：
2018-01-01
影响因子：
4.6
通讯作者：
Yoo, Hye Jin
中科院分区：
文献类型：
--
作者：
Hwang, Hwan-Jin;Kim, Joo Won;Yoo, Hye Jin
Sestrin 2（sesn 2）是一种内源性抗氧化蛋白，最近因其治疗各种炎症性疾病的潜力而受到关注。然而，sesn 2与心肌病的关系尚不清楚。在H9 c2细胞中，sesn 2敲低降低了5'腺苷一磷酸活化蛋白激酶（AMPK）磷酸化水平，下调了包括过氧化氢酶和超氧化物歧化酶（SOD 2）在内的抗氧化基因，并增加了脂多糖（LPS）处理后的活性氧（ROS）产生。LPS介导的细胞死亡和基质金属蛋白酶（MMP）2和MMP 9的表达显着增加sesn 2敲低。然而，这些增加被5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR），AMPK激活剂治疗。与体外结果一致，与对照C57 BL/6小鼠的心脏组织相比，sesn 2敲除小鼠的心脏组织中AMPK磷酸化降低，这与抗氧化基因表达降低和LPS介导的细胞死亡信号增加有关。此外，在C57 BL/6小鼠的心脏组织中，sesn 2敲低引起的AMPK磷酸化的减少增加了LPS介导的心脏纤维化因子的表达，包括I型和III型胶原蛋白以及MMP 2和MMP 9。这些结果表明，sesn 2是一个新的潜在的治疗靶点，在炎症条件下的心肌病。
Sestrin2 (sesn2) is an endogenous antioxidant protein that has recently gained attention for its potential to treat various inflammatory diseases. However, the relationship of sesn2 with cardiomyopathy is still unclear. In H9c2 cells, sesn2 knockdown reduced the level of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, downregulated antioxidant genes including catalase and superoxide dismutase (SOD2), and increased reactive oxygen species (ROS) production upon lipopolysaccharide (LPS) treatment. LPS-mediated cell death and the expression of matrix metalloproteinase (MMP) 2 and MMP9 were significantly increased by sesn2 knockdown. However, these increases were prevented by treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator. Consistent with the in vitro results, AMPK phosphorylation was decreased in heart tissue from sesn2 knockdown mice compared to heart tissue from control C57BL/6 mice, which was associated with decreased expression of antioxidant genes and increased LPS-mediated cell death signaling. Furthermore, the decrease in AMPK phosphorylation caused by sesn2 knockdown increased LPS-mediated expression of cardiac fibrotic factors, including collagen type I and type III, in addition to MMP2 and MMP9, in heart tissue from C57BL/6 mice. These results suggest that sesn2 is a novel potential therapeutic target for cardiomyopathy under inflammatory conditions.