MicroRNA-21 protects neurons from ischemic death.
MicroRNA-21 protects neurons from ischemic death.
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DOI：
10.1111/j.1742-4658.2010.07818.x
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Buller B;Liu X;Wang X;Zhang RL;Zhang L;Hozeska-Solgot A;Chopp M;Zhang ZG
microRNA（miRNA）是一类小分子RNA，通过与靶mRNA的3′UTR互补结合而减弱蛋白质的表达。目前，关于脑缺血后miRNA的研究还很少。特别是，miR-21在某些生物系统中是一种强抗凋亡因子。我们研究了miR-21在大鼠卒中后的作用。我们采用原位杂交（ISH）和激光捕获显微切割（LCM）结合实时荧光定量RT-PCR的方法研究了脑卒中后miR-21的表达。ISH显示，miR-21表达在缺血边界区（IBZ）的神经元中上调，定量实时RT-PCR分析显示，与中风后2天（n=4; P<0.05）和7天（n=3; P<0.05）的同源对侧神经元相比，中风使通过LCM从IBZ分离的神经元中的成熟miR-21水平增加约3倍。在体外培养的皮层神经元中，miR-21的过表达显著抑制了氧和葡萄糖剥夺（OGD）诱导的凋亡性细胞死亡，而通过反义抑制内源性miR-21的衰减加剧了OGD后的细胞死亡。此外，神经元中miR-21的过表达显著降低了Faslg蛋白水平，并且将miR-21模拟物引入293-HEK细胞中显著降低了含有Faslg 3′非翻译区的报告系统中的荧光素酶活性。我们的数据表明，miR-21的过表达可防止缺血性神经元死亡，并且miR-21靶向的Fas lg（TNFα家族成员和重要的细胞死亡诱导配体）的下调可能介导神经保护作用。这些新的发现表明miR-21可能是治疗中风的有吸引力的治疗分子。
MicroRNAs (miRNA) are small RNAs that attenuate protein expression by complementary binding to the 3′UTR of a target mRNA. Currently, very little is known about miRNA after cerebral ischemia. In particular, miR-21 is a strong antiapoptotic factor in some biological systems. We investigated the role of miR-21 after stroke in rat. We employed in situ hybridization (ISH) and laser capture microdissection (LCM) in combination with real-time RT-PCR to investigate the expression of miR-21 after stroke. ISH revealed that miR-21 expression was upregulated in neurons of the ischemic boundary zone (IBZ), and quantitative real-time RT-PCR analysis revealed that stroke increased mature miR-21 levels by ~3 fold in neurons isolated from the IBZ by LCM compared to homologous contralateral neurons 2 (n=4; P<0.05) and 7(n=3; P<0.05) days after stroke. In vitro, overexpression of miR-21 in cultured cortical neurons substantially suppressed oxygen and glucose deprivation (OGD)-induced apoptotic cell death, whereas attenuation of endogenous miR-21 by antisense inhibition exacerbated cell death after OGD. Moreover, overexpression of miR-21 in neurons significantly reduced Faslg protein levels and introduction of a miR-21 mimic into 293-HEK cells substantially reduced luciferase activity in a reporter system containing the 3′ untranslated region of Faslg. Our data indicate that overexpression of miR-21 protects against ischemic neuronal death and that downregulation of Faslg, a TNFα family member and an important cell death inducing ligand, targeted by miR-21 likely mediates the neuroprotective effect. These novel findings suggest that miR-21 may be an attractive therapeutic molecule for treament of stroke.
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