TRIM25 activates Wnt/β-catenin signalling by destabilising MAT2A mRNA to drive thoracic aortic aneurysm development.

IF 3.1 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chaojie Li, Kan Wang, Jian Fang, Lin Qin, Qiong Ling, Yu Yu
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引用次数: 0

Abstract

This study explored the roles of methionine adenosyltransferase 2A (MAT2A) and tripartite motif containing 25 (TRIM25) in the progression of thoracic aortic aneurysm (TAA). The TAA model was established based on the β-aminopropionitrile method. The effects of MAT2A on thoracic aortic lesions and molecular levels were analyzed by several pathological staining assays (hematoxylin-eosin, Verhoeff-Van Gieson, TUNEL) and molecular biology experiments (qRT-PCR, Western blot). Angiotensin II (Ang-II) was used to induce injury in vascular smooth muscle cells (VSMCs) in vitro. The effects of MAT2A, shMAT2A, shTRIM25 and/or Wnt inhibitor (IWR-1) on the viability, apoptosis and protein expressions of VSMCs were examined by CCK-8, Annexin V-FITC/PI and Western blot assays. In TAA mice, overexpression of MAT2A alleviated thoracic aortic injury, inhibited the aberrant expressions of aortic contractile proteins and dedifferentiation markers, and blocked the activation of Wnt/β-catenin pathway. In Ang-II-induced VSMCs, up-regulation of MAT2A increased cellular activity and repressed the expression of β-catenin protein. TRIM25 knockdown promoted activity of VSMCs, inhibited apoptosis, and blocked the Wnt/β-catenin pathway activation by binding to MAT2A. IWR-1 partially counteracted the regulatory effects of shMAT2A. Collectively, TRIM25 destabilises the mRNA of MAT2A to activate Wnt/β-catenin signaling and ultimately exacerbate TAA injury.

TRIM25 通过破坏 MAT2A mRNA 的稳定性来激活 Wnt/β-catenin 信号,从而推动胸主动脉瘤的发展。
本研究探讨了蛋氨酸腺苷基转移酶2A(MAT2A)和含三方基序25(TRIM25)在胸主动脉瘤(TAA)进展中的作用。根据β-氨基丙腈法建立了TAA模型。通过几种病理染色法(苏木精-伊红、Verhoeff-Van Gieson、TUNEL)和分子生物学实验(qRT-PCR、Western blot)分析了MAT2A对胸主动脉病变和分子水平的影响。血管紧张素 II(Ang-II)用于体外诱导血管平滑肌细胞(VSMC)损伤。通过CCK-8、Annexin V-FITC/PI和Western印迹检测MAT2A、shMAT2A、shTRIM25和/或Wnt抑制剂(IWR-1)对血管平滑肌细胞活力、凋亡和蛋白表达的影响。在 TAA 小鼠中,过表达 MAT2A 可减轻胸主动脉损伤,抑制主动脉收缩蛋白和去分化标志物的异常表达,阻断 Wnt/β-catenin 通路的激活。在Ang-II诱导的VSMCs中,MAT2A的上调增加了细胞活性并抑制了β-catenin蛋白的表达。TRIM25 敲除可促进 VSMC 的活性,抑制细胞凋亡,并通过与 MAT2A 结合阻断 Wnt/β-catenin 通路的激活。IWR-1 部分抵消了 shMAT2A 的调控作用。总之,TRIM25会破坏MAT2A mRNA的稳定性,从而激活Wnt/β-catenin信号,最终加剧TAA损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Human molecular genetics
Human molecular genetics 生物-生化与分子生物学
CiteScore
6.90
自引率
2.90%
发文量
294
审稿时长
2-4 weeks
期刊介绍: Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.
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