Journal Article

Remdesivir inhibits endothelial activation and atherosclerosis by coupling TAL1 to TRAF6

Li, Ruru, Li, Li, Li, Min, Hu, Shunxin, Wu, Zongyin, Huo, Qianqian, Ren, Changjie, Zhang, Hanning, Zhang, Chenghu

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute lymphoblastic leukemia / Adenosine Monophosphate - analogs & derivatives / Adenosine Monophosphate - pharmacology / Adenosine Monophosphate - therapeutic use / Alanine - analogs & derivatives / Alanine - pharmacology / Alanine - therapeutic use / Analysis / Analysis and chemistry / Animals / Aorta / Aorta - drug effects / Aorta - pathology / Apolipoprotein E / Apolipoproteins E - deficiency / Apolipoproteins E - metabolism / Arteriosclerosis / Atherosclerosis / Atherosclerosis - drug therapy / Atherosclerosis - metabolism / Atherosclerosis - pathology / Basic Helix-Loop-Helix Transcription Factors - metabolism / Biomedical and Life Sciences / Biomedicine / Blood / Cardiovascular / Care and treatment / Cell activation / Cell adhesion & migration / Cell Adhesion - drug effects / Cell adhesion molecules / Coronary vessels / Disease / Drug therapy / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Endothelial Cells - pathology / Human Umbilical Vein Endothelial Cells - drug effects / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Immunoprecipitation / Inflammation / Intercellular adhesion molecule 1 / Kinases / Leukemia / Ligands / Lipids / Lipoproteins / Lipoproteins, LDL - pharmacology / Low density lipoprotein / Lymphatic leukemia / Lymphocytes T / Male / Medical innovations / Medicine/Public Health / Metabolic and Lipoprotein Translation / Mice / Mice, Inbred C57BL / Monocytes / Overexpression / Oxidative stress / Patient outcomes / Protein Binding - drug effects / Proteins / Reactive oxygen species / Reactive Oxygen Species - metabolism / RNA polymerase / Severe acute respiratory syndrome coronavirus 2 / siRNA / TNF Receptor-Associated Factor 6 - metabolism / TRAF6 protein / Tumor necrosis factor / Tumor necrosis factor receptors / Ubiquitin-protein ligase / Ubiquitination / Ubiquitination - drug effects / Umbilical vein / Vascular cell adhesion molecule 1 / Vascular Cell Adhesion Molecule-1 - metabolism