Department of Cardiothoracic Surgery, People's Hospital of Xiangzhou District, No. 178 Lanpu Road, Xiangzhou District, Zhuhai, Guangdong, 519000, China.
Department of Cardiothoracic Surgery, the Second Clinical College, Guangzhou University of Chinese Medicine, No. 111, Dade Road, Yuexiu District, Guangzhou, Guangdong, 510120, China.
Hum Mol Genet. 2024 Nov 5;33(21):1890-1899. doi: 10.1093/hmg/ddae122.
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.
本研究探讨了蛋氨酸腺苷转移酶 2A（MAT2A）和三肽基含 25 个氨基酸（TRIM25）在胸主动脉瘤（TAA）进展中的作用。采用β-氨基丙腈法建立 TAA 模型。通过几种病理染色（苏木精-伊红、Verhoeff-Van Gieson、TUNEL）和分子生物学实验（qRT-PCR、Western blot）分析 MAT2A 对胸主动脉病变和分子水平的影响。采用血管紧张素 II（Ang-II）体外诱导血管平滑肌细胞（VSMCs）损伤。通过 CCK-8、Annexin V-FITC/PI 和 Western blot 检测 MAT2A、shMAT2A、shTRIM25 和/或 Wnt 抑制剂（IWR-1）对 VSMCs 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，并阻断 Wnt/β-catenin 通路的激活。在 Ang-II 诱导的 VSMCs 中，上调 MAT2A 可增加细胞活力并抑制β-catenin 蛋白的表达。TRIM25 敲低促进了 VSMCs 的活性，抑制了凋亡，并通过与 MAT2A 结合阻断了 Wnt/β-catenin 通路的激活。IWR-1 部分抵消了 shMAT2A 的调节作用。综上所述，TRIM25 使 MAT2A 的 mRNA 不稳定，从而激活 Wnt/β-catenin 信号通路，最终加重 TAA 损伤。
