Up-regulation of miR-325-3p suppresses pineal aralkylamine N-acetyltransferase (Aanat) after neonatal hypoxia-ischemia brain injury in rats
Up-regulation of miR-325-3p suppresses pineal aralkylamine N-acetyltransferase (Aanat) after neonatal hypoxia-ischemia brain injury in rats
复制标题
大鼠新生儿缺氧缺血性脑损伤后 miR-325-3p 上调抑制松果体芳烷基胺 N-乙酰转移酶 (Aanat)
DOI：
10.1016/j.brainres.2017.05.001
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发表时间：
2017-08-01
期刊：
影响因子：
2.9
通讯作者：
Ding, Xin
中科院分区：
文献类型：
--
作者：
Yang, Yuanyuan;Sun, Bin;Ding, Xin
缺氧缺血性脑损伤（HIBD）的幸存者，除了精神发育障碍外，还经常发生昼夜节律紊乱，尽管其潜在机制在很大程度上尚不清楚。在这里，我们首先验证了松果体芳烷基胺N-乙酰转移酶（Aanat），褪黑激素（MT）合成的关键调节剂，沿着MT的mRNA和蛋白质表达在HIBD后严重受损。此外，我们证明，新生儿缺氧缺血性脑损伤破坏了幼年大鼠运动活动的昼夜节律。基于HIBD后miRNA表达变化的高通量筛选的生物信息学分析（Ding et al.，2015），我们鉴定了一种microRNA，miR-325 - 3p，作为负责HIBD后Aanat下调的潜在候选者。荧光素酶报告基因分析表明，miR-325 - 3p和Aanat mRNA 3'-UTR之间的特异性相互作用阻断了培养的松果体细胞中去甲肾上腺素（NE）诱导的Aanat活化。此外，miR-325 - 3p抑制部分挽救了NE对Aanat的诱导，这在氧葡萄糖剥夺下显著降低。通过阐明松果体miR-325 - 3p对损伤后Aanat表达的作用，我们的研究为HIBD后昼夜节律功能障碍的病理生理机制和潜在的治疗靶点提供了新的见解。(C)2017爱思唯尔B.V.保留所有权利。
Survivors of hypoxic-ischemic brain damage (HIBD), besides impairment of psychomotor development, often develop circadian rhythm disorders, although the underlying mechanisms are largely unknown. Here, we first verified that mRNA and protein expression of pineal aralkylamine N-acetyltransferase (Aanat), a key regulator for melatonin (MT) synthesis, along with MT, were severely impaired after HIBD. In addition, we demonstrated that neonatal HIBD disrupted the circadian rhythmicity of locomotor activities in juvenile rats. Based on bioinformatics analysis of a high throughput screening of miRNA expression changes after HIBD (Ding et al., 2015), we identified one microRNA, miR-325-3p, as a potential candidate responsible for the down regulation of Aanat after HIBD. Luciferase reporter assays demonstrated a specific interaction between miR-325-3p and Aanat mRNA 3'-UTR miR-325-3p blocked norepinephrine (NE) induced Aanat activation in cultured pinealocytes. In addition, miR-325-3p inhibition partially rescued Aanat induction by NE, which was significantly reduced under oxygen glucose deprivation. By elucidating the role of pineal miR-325-3p on Aanat expression upon injury, our study provides new insights into the pathophysiological mechanisms of circadian dysfunction and potential therapeutic targets after HIBD. (C) 2017 Elsevier B.V. All rights reserved.