mir-193 targets ALDH2 and contributes to toxic aldehyde accumulation and tyrosine hydroxylase dysfunction in cerebral ischemia/reperfusion injury.
mir-193 targets ALDH2 and contributes to toxic aldehyde accumulation and tyrosine hydroxylase dysfunction in cerebral ischemia/reperfusion injury.
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mir-193 以 ALDH2 为靶点，导致脑缺血/再灌注损伤中有毒醛积聚和酪氨酸羟化酶功能障碍
DOI：
10.18632/oncotarget.21129
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发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Yang ZB
中科院分区：
文献类型：
--
作者：
Mao L;Zuo ML;Hu GH;Duan XM;Yang ZB
MicroRNAs(miRNAs，miR)在脑缺血再灌注(I/R)损伤中起重要作用。然而，miRNAs在有毒醛和酪氨酸积累中的作用还没有完全阐明。我们建立了大鼠脑I/R模型，发现miR-193的过度表达与4-羟基壬烯醛(4-HNE)、丙二醛(MDA)和酪氨酸的积累有关，而与乙醛脱氢酶(ALDH2)、酪氨酸羟化酶(TH)和多巴胺的减少有关。为了揭示miR-193介导的上述I/R损伤表型的分子机制，我们进行了生物信息学分析，发现ALDH2是miR-193的潜在靶点。通过体外实验(如miR-193模拟/抑制基因转染法、荧光素酶报告基因质粒转染法、4-HNE暴露实验)和体内输注miR-193琼脂糖凝胶实验，我们证明miR-193直接抑制ALDH2的表达，导致毒性醛蓄积，导致酪氨酸羟化酶功能障碍。本研究表明，在大鼠模型中，miR-193的过表达加剧了脑损伤，这是由于以下一系列的过程：靶向抑制ALDH2，醛积累，酪氨酸羟化酶功能障碍，导致酪氨酸积累和多巴胺合成不足。
MicroRNAs (miRNAs, miR) play a fundamental role in cerebral ischemia/reperfusion (I/R) injury. However, the role of miRNAs in toxic aldehyde and tyrosine accumulation is not fully elucidated. We constructed a cerebral I/R rat model and found that overexpression of miR-193 was associated with the accumulation of 4-Hydroxynonenal (4-HNE), Malondialdehyde (MDA), and tyrosine, and with the decrease of aldehyde dehydrogenase (ALDH2), tyrosine hydroxylase (TH), and dopamine. To unveil the molecular mechanism of the miR-193-mediated phenotype in I/R injury as described above, we performed bioinformatic analysis and found that ALDH2 was a potential target of miR-193. Through in vitro experiments (such as miR-193 mimic/inhibitor transfection, luciferase reporter gene plasmid transfection, and 4-HNE exposure) and in vivo infusion of miR-193 agomir, we demonstrated that miR-193 directly suppressed the expression of ALDH2 and led to toxic aldehyde accumulation, resulting in dysfunction of tyrosine hydroxylase. The present study suggests that the overexpression of miR-193 in a rat model exacerbated brain injury due to the following sequential process: targeted suppression of ALDH2, aldehyde accumulation, and tyrosine hydroxylase dysfunction, leading to tyrosine accumulation and insufficiency of dopamine synthesis.