Wang Wenjun, Chen Jiayi, Lai Songqing, Zeng Ruiyuan, Fang Ming, Wan Li, Li Yiying
Department of Cardiovascular Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
The First Clinical Medical College of Nanchang University, Nanchang, People's Republic of China.
Am J Physiol Cell Physiol. 2025 Feb 1;328(2):C387-C399. doi: 10.1152/ajpcell.00577.2024. Epub 2024 Dec 13.
Thoracic aortic aneurysm (TAA) is a vascular disease associated with high mortality rates. Ferroptosis has been shown to mediate the transformation of vascular smooth muscle cells (VSMCs). However, the regulatory mechanisms by which ferroptosis influences TAA remain unclear. In this study, we induced TAA mouse models using angiotensin II (Ang II) and evaluated the impact of ferroptosis on the pathological changes observed in TAA mice, employing liproxstatin-1 as a treatment. In addition, we assessed the regulatory effect of METTL14 on the ferroptosis of VSMCs after treating them with a ferroptosis activator (imidazole ketone erastin, IKE). RNA binding protein immunoprecipitation (RIP) and RNA pull-down assays were conducted to investigate the interaction between acyl-CoA synthase long-chain family member 4 () mRNA and the proteins METTL14 or IGF2BP2. The results indicated that the level of ferroptosis was elevated in the thoracic aorta of TAA mice, and METTL14 was upregulated in TAA models and IKE-induced VSMCs. Knockdown of METTL14 was found to inhibit the progression of TAA by reducing the ferroptosis of VSMCs. Furthermore, IGF2BP2 recognized METTL14-modified mRNA and regulated its stability, thereby mediating the ferroptosis of VSMCs. Collectively, the effects of METTL14 on VSMC ferroptosis present therapeutic potential for the treatment of TAA. Our study confirmed that METTL14 can induce ferroptosis in vascular smooth muscle cells during the progression of thoracic aortic aneurysm by mediating the mA modification of mRNA.
胸主动脉瘤（TAA）是一种死亡率很高的血管疾病。铁死亡已被证明可介导血管平滑肌细胞（VSMC）的转化。然而，铁死亡影响TAA的调控机制仍不清楚。在本研究中，我们使用血管紧张素II（Ang II）诱导TAA小鼠模型，并使用liproxstatin-1作为治疗手段，评估铁死亡对TAA小鼠病理变化的影响。此外，我们在用铁死亡激活剂（咪唑酮厄拉司丁，IKE）处理VSMC后，评估了METTL14对其铁死亡的调控作用。进行了RNA结合蛋白免疫沉淀（RIP）和RNA下拉实验，以研究酰基辅酶A合成酶长链家族成员4（）mRNA与METTL14或IGF2BP2蛋白之间的相互作用。结果表明，TAA小鼠胸主动脉中的铁死亡水平升高，且METTL14在TAA模型和IKE诱导的VSMC中上调。发现敲低METTL14可通过减少VSMC的铁死亡来抑制TAA的进展。此外，IGF2BP2识别METTL14修饰的mRNA并调节其稳定性，从而介导VSMC的铁死亡。总的来说，METTL14对VSMC铁死亡的影响为TAA的治疗提供了潜在的治疗价值。我们的研究证实，METTL14可通过介导mRNA的m⁶A修饰在胸主动脉瘤进展过程中诱导血管平滑肌细胞发生铁死亡。
