Zhang Hanning, Li Ruru, Huo Qianqian, Li Li, Li Min, Hu Shunxin, Ren Changjie, Wu Zongyin, Zhang Chenghu
Shandong First Medical University, Jinan, China.
Department of Cardiology, Jining First People's Hospital, Shandong First Medical University, No. 6 Jiankang Road, Jining, 272000, Shandong, China.
J Transl Med. 2025 Jul 1;23(1):719. doi: 10.1186/s12967-025-06673-2.
BACKGROUND: Atherosclerosis is characterized by complex pathological processes, including endothelial dysfunction and inflammation. The underlying pathogenic mechanisms have been well elucidated; however, effective treatments are yet to be validated. Our study explored the novel application of a recognized antiviral agent, remdesivir, focusing on its impact on endothelial activation and atherosclerosis. METHODS: Pharmacological treatment with remdesivir significantly reduced atherosclerotic lesions in the total aorta and decreased VCAM-1 expression in aortic roots of ApoE-/- mice. Remdesivir notably attenuated ox-LDL-induced endothelial cell (EC) activation, monocyte adhesion, and ROS production. In HUVECs, TAL1 interference via siRNA significantly increased TRAF6 protein levels, which was reversed by remdesivir. Remdesivir also reduced both total and K63-linked ubiquitination of TRAF6 in HUVECs. Immunoprecipitation assays revealed diminished co-localization of the two proteins under ox-LDL treatment, but this effect was reversed by remdesivir. Importantly, ectopic adeno-associated virus (AAV)-mediated overexpression of TAL1 reduced atherosclerotic lesions and VCAM-1 expression in the aorta of ApoE-/- mice. RESULTS: In ApoE mice fed with a Western diet, remdesivir greatly attenuated atherosclerosis progression. At the cellular level, remdesivir suppressed oxidative stress, THP-1 adhesion, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 via oxidized low-density lipoprotein in human umbilical vein endothelial cells. T-cell acute lymphoblastic leukemia 1 (TAL1) functions by interacting with the ubiquitin E3 ligase TNF receptor-associated factor 6 (TRAF6) to ubiquitinate TRAF6, inhibiting nuclear factor kappa B activation. Remdesivir also restored the TAL1-TRAF6 interaction and decreased endothelial activation. Endothelial-specific TAL1 over-expression in ApoE mice significantly reduced aortic plaque formation. CONCLUSIONS: Remdesivir impedes atherosclerosis progression by re-establishing the interaction between TAL1 and TRAF6, diminishing endothelial activation. These findings offer an innovative therapeutic approach for atherosclerosis.
背景：动脉粥样硬化具有复杂的病理过程，包括内皮功能障碍和炎症。其潜在的致病机制已得到充分阐明；然而，有效的治疗方法尚未得到验证。我们的研究探索了一种公认的抗病毒药物瑞德西韦的新应用，重点关注其对内皮激活和动脉粥样硬化的影响。 方法：用瑞德西韦进行药物治疗可显著减少ApoE基因敲除小鼠主动脉中的动脉粥样硬化病变，并降低主动脉根部血管细胞黏附分子-1（VCAM-1）的表达。瑞德西韦显著减弱了氧化型低密度脂蛋白（ox-LDL）诱导的内皮细胞（EC）激活、单核细胞黏附及活性氧（ROS）生成。在人脐静脉内皮细胞（HUVECs）中，通过小干扰RNA（siRNA）干扰T细胞急性淋巴细胞白血病1（TAL1）可显著增加肿瘤坏死因子受体相关因子6（TRAF6）蛋白水平，而瑞德西韦可使其逆转。瑞德西韦还降低了HUVECs中TRAF6的总泛素化及K63连接的泛素化。免疫沉淀分析显示，在ox-LDL处理下，这两种蛋白的共定位减少，但瑞德西韦可使其逆转。重要的是，异位腺相关病毒（AAV）介导的TAL1过表达减少了ApoE基因敲除小鼠主动脉中的动脉粥样硬化病变及VCAM-1表达。 结果：在喂食西方饮食的ApoE小鼠中，瑞德西韦极大地减缓了动脉粥样硬化的进展。在细胞水平上，瑞德西韦通过人脐静脉内皮细胞中的氧化型低密度脂蛋白抑制氧化应激、THP-1黏附、血管细胞黏附分子1及细胞间黏附分子1。TAL1通过与泛素E3连接酶TRAF6相互作用使TRAF6泛素化，从而抑制核因子κB激活发挥作用。瑞德西韦还恢复了TAL1-TRAF6相互作用并减少了内皮激活。ApoE小鼠内皮特异性TAL1过表达显著减少了主动脉斑块形成。 结论：瑞德西韦通过重新建立TAL1与TRAF6之间的相互作用，减少内皮激活，从而阻碍动脉粥样硬化进展。这些发现为动脉粥样硬化提供了一种创新的治疗方法。
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