USP18 ameliorates atherosclerosis through inhibiting the activation of TAK1

Atherosclerosis is a chronic inflammatory condition marked by the deposition of lipids within the arterial wall and the infiltration of inflammatory cells, culminating in the development of atherosclerotic plaques. Ubiquitin-specific protease 18, USP18, a specific deubiquitinating enzyme, has been demonstrated to exert protective effects on the cardiovascular system.

Pathological studies were performed utilizing human coronary arteries obtained from the Forensic Medical Examination Center of Guizhou Medical University, in conjunction with the aorta from experimental ApoE knockout mice. The ApoE knockout mice underwent intervention with adenovirus carrying USP18-RNAi and a control adenovirus containing hU6-MCS-CMV-EGFP, after which pathological analyses were conducted. In vitro, THP-1 cells, induced with phorbol ester, were subjected to treatment with si-USP18 or si-NC, followed by exposure to oxidized low-density lipoprotein. The expression levels of USP18 and proteins associated with the TAK1/NF-κB signaling pathway, as well as the interaction between USP18 and TAK1, were assessed using Western blotting, RT-PCR, and immunofluorescence techniques.The interaction between USP18 and TAK1 was confirmed using molecular docking techniques, co-immunoprecipitation assays, and immunofluorescence analysis.

The purpose of this study is to explore the role of USP18 on atherosclerosis and the underlying mechanism.

The expression of USP18 is elevated in early-stage human coronary atherosclerotic plaques but decreases in advanced lesions. Treatment of macrophages derived from THP-1 cells and bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS) results in reduced USP18 expression. In ApoE^-/- mice, USP18 knockdown leads to an increase in the atherosclerotic necrotic core area, which significantly enhances inflammation and macrophage infiltration within the aorta. In vitro experiments indicated that the suppression of USP18 expression in macrophages derived from THP-1 cells, followed by treatment with oxidized low-density lipoprotein (ox-LDL), enhances lipid uptake and inflammatory responses. Furthermore, USP18 silencing enhances the phosphorylation of key kinases and the upstream regulator TAK1 within the NF-κB signaling pathway in macrophages. USP18 inhibits TAK1 phosphorylation by binding to and deubiquitinating TAK1, thereby suppressing NF-κB pathway activation. The enhancement of the NF-κB signaling pathway in macrophages due to USP18 silencing is mitigated by TAK1 inhibitors.

USP18 modulates TAK1 to suppress the activation of the NF-κB signaling pathway in macrophages, consequently exerting an anti-atherosclerotic effect and offering a potential therapeutic strategy for atherosclerosis treatment.