Dhiraj Dalbir K, Chrysanthou Elvina, Mallucci Giovanna R, Bushell Martin
MRC Toxicology Unit, Medical Research Council, Leicester, England, United Kingdom.
PLoS One. 2013 Dec 20;8(12):e83717. doi: 10.1371/journal.pone.0083717. eCollection 2013.
Stroke, the loss of neurons after ischemic insult to the brain, is one of the leading causes of death and disability worldwide. Despite its prevalence and severity, current therapy is extremely limited, highlighting the importance of further understanding the molecular events underlying ischemia-induced neuronal cell death. An ischemic area can be subdivided into two separate pathophysiological regions: the rapidly dying necrotic core, and the potentially salvageable apoptotic penumbra. Understanding molecular events occurring in the apoptotic ischemic penumbra may give greater insight into mechanisms controlling this salvageable tissue. miRNAs are known to have key roles in the regulation of gene expression in numerous pathological conditions, including the modulation of distinct pathways in stroke. However, previous studies have profiled miRNAs in the whole ischemic infarct, and do not differentiate between miRNA regulation in the necrotic core versus the apoptotic penumbra. We asked if there were unique miRNAs that are differentially regulated following ischemic insults in the salvageable apoptotic penumbra. miRNA expression profiles were compared in the whole infarct from in vivo stroke models, using the three vessel occlusion approach, to an in vitro model of the ischemic penumbra, prior to apoptotic induction. Multiple miRNAs were found to be differentially regulated following ischemic insults in each system. However, miR-19b, miR-29b-2* and miR-339-5p were significantly up-regulated in both model systems. Further, we confirmed these results in a neuroblastoma cell line subjected to a penumbra-like ischemic insult that induced the apoptotic cell death pathway. The data show that miR-19b, miR-29b-2* and miR-339-5p are up-regulated following ischemic insults and may be regulating gene expression to control important cellular pathways in the salvageable ischemic penumbra. Further investigation of their role and mRNA target identification may lead to new insights into the molecular mechanisms taking place in the salvageable apoptotic penumbra.
中风，即脑部缺血性损伤后神经元的丧失，是全球范围内导致死亡和残疾的主要原因之一。尽管其发病率高且病情严重，但目前的治疗方法极为有限，这凸显了进一步了解缺血诱导的神经元细胞死亡背后分子事件的重要性。缺血区域可细分为两个独立的病理生理区域：迅速死亡的坏死核心区和可能可挽救的凋亡半暗带。了解凋亡性缺血半暗带中发生的分子事件，可能会更深入地洞察控制这一可挽救组织的机制。已知微小RNA（miRNA）在多种病理状况下的基因表达调控中发挥关键作用，包括在中风中调节不同的信号通路。然而，先前的研究对整个缺血梗死区域的miRNA进行了分析，并未区分坏死核心区与凋亡半暗带中miRNA的调控情况。我们探究了在可挽救的凋亡半暗带中，缺血性损伤后是否存在独特的、差异表达的miRNA。我们采用三血管闭塞法，将体内中风模型整个梗死区域的miRNA表达谱与凋亡诱导前缺血半暗带的体外模型进行了比较。在每个系统中，发现多种miRNA在缺血性损伤后存在差异表达。然而，miR-19b、miR-29b-2和miR-339-5p在两个模型系统中均显著上调。此外，我们在经历了类似半暗带缺血性损伤并诱导凋亡细胞死亡途径的神经母细胞瘤细胞系中证实了这些结果。数据表明，miR-19b、miR-29b-2和miR-339-5p在缺血性损伤后上调，可能正在调节基因表达以控制可挽救的缺血半暗带中的重要细胞信号通路。对它们的作用及mRNA靶点的进一步研究，可能会为可挽救的凋亡半暗带中发生的分子机制带来新的见解。
