Salvianolic acid A alleviates atherosclerosis by inhibiting inflammation through Trc8-mediated 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation

Background: 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. Purpose: We aimed to determine whether SalA prevents atherosclerosis by modulating 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) degradation via the ubiquitin-proteasomal pathway. Methods: 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. Results: 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-alpha (TNF-alpha), interleukin (IL)-18, 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. Conclusion: SalA rescues atherosclerosis by inhibiting inflammation through the Trc8-regulated degradation of HMGCR. These findings underscore Trc8 as a potential target of atherosclerosis.