Salvianolic acid A alleviates atherosclerosis by inhibiting inflammation through Trc8-mediated 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation
Dan Xie, Lijun Song, Xiang Dongyang, Xiangyu Gao, Wenchang Zhao
Abstract
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-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. Conclusion SalA rescues atherosclerosis by inhibiting inflammation through the Trc8-regulated degradation of HMGCR. These findings underscore Trc8 as a potential target of atherosclerosis.