MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage.
MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage.
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DOI：
10.1371/journal.pone.0058039
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Vemuganti R
中科院分区：
文献类型：
--
作者：
Pandi G;Nakka VP;Dharap A;Roopra A;Vemuganti R
最近的研究表明，中风广泛改变大脑microRNA（miRNA）的表达谱和一些miRNA在介导缺血病理生理学中发挥作用。我们目前评估了miR-29 c的意义，miR-29 c是啮齿动物脑中高度表达的miRNA，在成年大鼠局灶性缺血后以及PC 12细胞中氧-葡萄糖剥夺后显著下调。生物信息学研究表明，DNA甲基转移酶3a（DNMT 3a）是miR-29 c的主要靶点，与premiR-29 c共转染可抑制DNMT 3a 3′UTR载体的表达。在PC 12细胞中，用premIR-29 c处理阻止了OGD诱导的细胞死亡（58±6%; p<0.05）。此外，用EkomiR-29 c处理导致PC 12细胞中46±5%的细胞死亡。当用premIR-29 c处理大鼠并使其经受短暂局灶性缺血时，与对照premIR处理组相比，缺血后miR-29 c水平恢复并且梗塞体积显著减小（34±6%; p<0.05）。与相应的对照siRNA处理组相比，DNMT 3a siRNA处理还显著减少了PC 12细胞中的OGD后细胞死亡（54±6%; p<0.05），并减少了大鼠中的缺血后梗死体积（30±5%; p<0.05）。miR-29 c基因启动子显示转录因子REST的特异性结合位点，并且当与REST表达质粒共转染时，miR-29 c启动子载体表达被削减。此外，与对照siRNA处理相比，用REST siRNA处理阻止了PC 12细胞中缺血后miR-29 c下调和DNMT 3a诱导，并减少了缺血性细胞死亡（64±9%; p<0.05）。这些研究表明，miR-29 c是一种促存活的miRNA，其下调通过其靶点DNMT 3a起作用，是缺血性脑损伤的促进剂。此外，REST是miR-29 c的上游转录控制器，减少REST诱导可防止miR-29 c下调和缺血性神经元死亡。
Recent studies showed that stroke extensively alters cerebral microRNA (miRNA) expression profiles and several miRNAs play a role in mediating ischemic pathophysiology. We currently evaluated the significance of miR-29c, a highly expressed miRNA in rodent brain that was significantly down-regulated after focal ischemia in adult rats as well as after oxygen-glucose deprivation in PC12 cells. Bioinformatics indicated that DNA methyltransferase 3a (DNMT3a) is a major target of miR-29c and co-transfection with premiR-29c prevented DNMT3a 3′UTR vector expression. In PC12 cells, treatment with premiR-29c prevented OGD-induced cell death (by 58±6%; p<0.05). Furthermore, treatment with antagomiR-29c resulted in a 46±5% cell death in PC12 cells. When rats were treated with premiR-29c and subjected to transient focal ischemia, post-ischemic miR-29c levels were restored and the infarct volume decreased significantly (by 34±6%; p<0.05) compared to control premiR treated group. DNMT3a siRNA treatment also significantly curtailed the post-OGD cell death in PC12 cells (by 54±6%; p<0.05) and decreased the post-ischemic infarct volume in rats (by 30±5%; p<0.05) compared to respective control siRNA treated groups. The miR-29c gene promoter showed specific binding sites for the transcription factor REST and the miR-29c promoter vector expression was curtailed when cotransfected with a REST expressing plasmid. Furthermore, treatment with REST siRNA prevented the post-ischemic miR-29c down-regulation and DNMT3a induction in PC12 cells and curtailed ischemic cell death (by 64±9%; p<0.05) compared to control siRNA treatment. These studies suggest that miR-29c is a pro-survival miRNA and its down-regulation is a promoter of ischemic brain damage by acting through its target DNMT3a. Furthermore, REST is an upstream transcriptional controller of miR-29c and curtailing REST induction prevents miR-29c down-regulation and ischemic neuronal death.
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DOI：
10.1038/jcbfm.2008.157
发表时间：
2009-04
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
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影响因子：
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作者：
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期刊：
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影响因子：
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影响因子：
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