Deng Yang, Duan Rui, Hong Ye, Peng Qiang, Li Zhong-Yuan, Chen Xiang-Liang, Zhang Ying-Dong
Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, Nanjing, 210006, People's Republic of China.
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China.
J Inflamm Res. 2024 Oct 21;17:7441-7461. doi: 10.2147/JIR.S479154. eCollection 2024.
Vascular dementia (VaD) is the second most common dementia in the world. An increasing number of studies have demonstrated the important role of long non-coding RNAs (lncRNAs) in VaD. Our previous investigation demonstrated that Trimethylamine-N-oxide (TMAO) exacerbates cognitive impairment and neuropathological alterations in VaD rats. Thus, we hypothesized that TMAO could play an injury role in VaD by regulating lncRNAs.
The rats using the bilateral common carotid artery (2VO) model were administered TMAO (120 mg/kg) for 8 consecutive weeks, 4 weeks preoperatively and 4 weeks postoperatively. High-throughput sequencing was conducted to investigate the effects of TMAO treatment on lncRNA expression in rat hippocampus and bioinformatics analysis was performed to identify potential downstream targets. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of lncRNA fetal-lethal noncoding developmental regulatory RNA (Fendrr), miR-145-5p, and paxillin (PXN). Learning and spatial memory capacities were measured, as well as inflammatory factors. Nissl staining was used to observe neuronal injury in the CA1 area of the hippocampus. Furthermore, we used the Fendrr loss-of-function assay, miR-145-5p gain-of-function assays and PXN loss-of-function assay to explore the mechanisms by which TMAO acts on VaD.
TMAO administration upregulated lncRNA Fendrr expression in the rat hippocampus, while the damaging effects of TMAO were counteracted after knockdown of Fendrr. Fendrr exhibits highly expressed in 2VO rats and sponged miR-145-5p, which targets PXN. Silencing of Fendrr or PXN, or promotion of miR-145-5p improved neurological function injury, reduced neuronal damage, as well as repressed inflammation response. Inhibition of miR-145-5p abrogated up Fendrr knockdown mediated influence on 2VO rats.
The results of this study indicated that TMAO inhibits the miR-145-5p/PXN axis by increasing the Fendrr expression, thus exacerbating the development of VaD.
血管性痴呆（VaD）是世界上第二常见的痴呆症。越来越多的研究表明长链非编码RNA（lncRNA）在VaD中发挥重要作用。我们之前的研究表明，氧化三甲胺（TMAO）会加剧VaD大鼠的认知障碍和神经病理学改变。因此，我们假设TMAO可能通过调节lncRNA在VaD中发挥损伤作用。
采用双侧颈总动脉（2VO）模型的大鼠连续8周给予TMAO（120mg/kg），术前4周和术后4周给药。进行高通量测序以研究TMAO处理对大鼠海马lncRNA表达的影响，并进行生物信息学分析以鉴定潜在的下游靶点。采用逆转录定量聚合酶链反应（RT-qPCR）检测长链非编码RNA胎儿致死性非编码发育调节RNA（Fendrr）、miR-145-5p和桩蛋白（PXN）的水平。测量学习和空间记忆能力以及炎症因子。采用尼氏染色观察海马CA1区神经元损伤情况。此外，我们使用Fendrr功能缺失试验、miR-145-5p功能获得试验和PXN功能缺失试验来探讨TMAO作用于VaD的机制。
给予TMAO上调了大鼠海马中lncRNA Fendrr的表达，而在敲低Fendrr后，TMAO的损伤作用得到抵消。Fendrr在2VO大鼠中高表达，并可吸附miR-145-5p，而miR-145-5p以PXN为靶点。沉默Fendrr或PXN，或促进miR-145-5p的表达可改善神经功能损伤，减少神经元损伤，并抑制炎症反应。抑制miR-145-5p可消除Fendrr敲低对2VO大鼠的介导影响。
本研究结果表明，TMAO通过增加Fendrr的表达抑制miR-145-5p/PXN轴，从而加剧VaD的发展。
