Institute of Pediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, 510623, China.
Division of Neonatology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Changsha, Hunan, 410011, China.
Sci Rep. 2018 Sep 14;8(1):13813. doi: 10.1038/s41598-018-32189-5.
In humans, malnutrition during pregnancy results in intrauterine growth restriction (IUGR) and an increased risk of neurological morbidities; altered miRNA characteristics have been suggested to contribute to IUGR neurological pathogenesis. A miRNA microarray was used to identify differentially expressed miRNA molecules in the hippocampi of rats with IUGR. Five of the molecules in question were selectively validated using real-time PCR in rats with IUGR. We then investigated the role of miR-199a-5p in hippocampal pathology. Bioinformatics analysis results suggested that TNF-α, caspase-3 and SIRT1 were potential targets of miR-199a-5p. Changes in PI3K, SIRT1 and caspase-3 protein expressions levels in the hippocampus were confirmed by Western blot analysis (all P < 0.05). Studies using the pheochromocytoma cell line PC12 cells and primary neurons demonstrated that miR-199a-5p modulated PI3K, caspase-3 and SIRT1 expression. Additionally, there was an inverse correlation between miR-199a-5p and caspase-3 expression, though dual-luciferase reporter assays showed that caspase-3 is not a target of miR-199a-5p. We conclude that IUGR affects hippocampal miRNAs characteristics. Our results also indicated that aberrantly high expression levels of miR-199a-5p may play an important role in the pathogenesis of IUGR by regulating SIRT1 and PI3K.
在人类中，妊娠期间营养不良会导致宫内生长受限（IUGR）和神经发育障碍的风险增加；已经提出改变的 miRNA 特征有助于 IUGR 的神经发病机制。使用 miRNA 微阵列来鉴定 IUGR 大鼠海马中差异表达的 miRNA 分子。用实时 PCR 选择性地验证了这些分子中的五个。然后，我们研究了 miR-199a-5p 在海马病理学中的作用。生物信息学分析结果表明，TNF-α、caspase-3 和 SIRT1 是 miR-199a-5p 的潜在靶标。Western blot 分析证实了海马中 PI3K、SIRT1 和 caspase-3 蛋白表达水平的变化（均 P<0.05）。使用嗜铬细胞瘤细胞系 PC12 细胞和原代神经元进行的研究表明，miR-199a-5p 调节 PI3K、caspase-3 和 SIRT1 的表达。此外，miR-199a-5p 与 caspase-3 表达之间存在负相关，尽管双荧光素酶报告基因分析表明 caspase-3 不是 miR-199a-5p 的靶标。我们得出结论，IUGR 影响海马 miRNAs 特征。我们的结果还表明，miR-199a-5p 的异常高表达水平可能通过调节 SIRT1 和 PI3K 在 IUGR 的发病机制中发挥重要作用。
