动脉粥样硬化是最普遍的心血管疾病，仍然是全球死亡率和致死率的主要贡献者。丹酚酸A（SalA）是一种水溶性酚酸，对动脉粥样硬化有益。然而，SalA保护动脉粥样硬化的机制仍不清楚。 我们旨在确定SalA是否通过泛素-蛋白酶体途径调节3-羟基-3-甲基谷氨酰辅酶A还原酶（HMGCR）降解来预防动脉粥样硬化。通过将载脂蛋白E（ApoE）敲减小鼠暴露于高脂饮食（HFD）和将人类脐静脉内皮细胞（HUVECs）暴露于氧化低密度脂蛋白（ox-LDL）来建立动脉粥样硬化的动物和细胞模型，我们的研究结果表明，类似于阿托伐他汀，SalA抑制了ApoE-/-小鼠的动脉粥样硬化斑块形成，改善了血清脂质积累，并降低了胆固醇水平。此外，SalA保护HUVECs免受ox-LDL引起的细胞活力降低和脂质积累。机制研究表明，SalA减少了ApoE-/-小鼠和HUVECs中前炎症因子肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β和IL-6的产生，并增加了抗炎因子IL-10的生成，伴随着HMGCR泛素化和降解的转位在8号肾癌染色体（Trc8）、胰岛素诱导基因（Insig）1和Insig2中。此外，Trc8的沉默消除了SalA诱导的HMGCR降解和抗动脉粥样硬化活性。 SalA通过抑制炎症调节Trc8调控的HMGCR降解拯救动脉粥样硬化。这些发现强调Trc8作为动脉粥样硬化的潜在靶点。 版权所有，©2023 Elsevier GmbH。保留所有权利。

Atherosclerosis is the most prevalent cardiovascular disease and remains the major contributor to death and mortality globally. Salvianolic acid A (SalA) is a water-soluble phenolic acid that benefits atherosclerosis. However, the mechanisms of SalA protecting against atherosclerosis remain unclear.We aimed to determine whether SalA prevents atherosclerosis by modulating 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) degradation via the ubiquitin-proteasomal pathway.The animal and cellular models of atherosclerosis were established by subjecting apolipoprotein E (ApoE) knockout mice to a high-fat diet (HFD) and exposing human umbilical vein endothelial cells (HUVECs) to oxidized low-density lipoprotein (ox-LDL), respectively.Our results showed that similar to atorvastatin, SalA suppressed atherosclerotic plaque formation, improved serum lipid accumulation, and reduced cholesterol levels in HFD-fed ApoE-/- mice. Moreover, SalA protected HUVECs from ox-LDL-caused cell viability reduction and lipid accumulation. The mechanism study revealed that SalA reduced the production of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and augmented the generation of the anti-inflammatory cytokine IL-10 in ApoE-/- mice and HUVECs, accompanied by increased HMGCR ubiquitination and degradation via translocation in renal carcinoma on chromosome 8 (Trc8), insulin-induced gene (Insig)1 and Insig2. Furthermore, the knockdown of Trc8 abolished the SalA-induced HMGCR degradation and anti-atherosclerosis activity.SalA rescues atherosclerosis by inhibiting inflammation through the Trc8-regulated degradation of HMGCR. These findings underscore Trc8 as a potential target of atherosclerosis.Copyright © 2023 Elsevier GmbH. All rights reserved.