salvianolic-acid-a and Atherosclerosis

Salvianolic acid A (SAA) is the main active component of the classic anti-atherosclerotic drug Salvia miltiorrhiza Bunge. Inflammation-induced infiltration of monocyte/macrophages into the vascular wall is the initiating step in atherogenesis, and targeted blocking of this step may provide a promising avenue for the precise treatment of atherosclerosis. However, the effect of salvianolic acid A on macrophages is still unknown.. To evaluate the effect of SAA on macrophage infiltration and the underlying mechanism of SAA against atherosclerosis.. Vascular endothelial cells were stimulated with lipopolysaccharide (LPS) to simulate the inflammatory environment, and its effect on monocyte/macrophages was evaluated. Mass spectrometry was used to identify the proteins that play a key role and further validated them. LncRNA sequencing, western blot analysis, RNA immunoprecipitation, and RNA pulldown were used to elucidate the mechanism of SAA against atherosclerosis. Finally, ApoE. After LPS stimulation, the increased secretion of GRP78 recruits circulating monocyte/macrophages and drives monocyte/macrophage adhesion and invasion into the vascular intima to promote atherosclerosis progression. Interestingly, SAA exerts anti-atherosclerosis effects by inhibiting the secretion of GRP78. Further mechanistic studies indicated that SAA upregulates the expression of lncRNA NR2F2-AS1, which reverses the abnormal localization of the KDEL receptor (KDELR) caused by inflammation. It promotes the homing of GRP78 from the Golgi apparatus to the endoplasmic reticulum rather than secreting outside the cell.. SAA alleviates atherosclerosis by inhibiting GRP78 secretion via the lncRNA NR2F2-AS1-KDELR axis. The findings not only provide a new direction for the precise therapy of atherosclerosis based on secretory GRP78 but also elucidate the pharmacological mechanism of SAA against atherosclerosis, putting the foundation for further development and clinical application of SAA drugs.

Topics: Animals; Atherosclerosis; Endoplasmic Reticulum Chaperone BiP; Endothelial Cells; Inflammation; Lipopolysaccharides; Mice; RNA, Long Noncoding

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. SalA rescues atherosclerosis by inhibiting inflammation through the Trc8-regulated degradation of HMGCR. These findings underscore Trc8 as a potential target of atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cytokines; Endothelial Cells; Humans; Inflammation; Mice; Mice, Knockout

Topics: Alkenes; Animals; Atherosclerosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Inflammasomes; Lipids; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Polyphenols; Rats; Rats, Zucker

The CC chemokine ligand-20 (CCL-20)/macrophage inflammatory protein-3α has been seen as one of the most important chemokines and played a key role in atherogenesis, but the mechanism that underlies the regulation of CCL-20 has not been established clearly yet. The aim of this study was to investigate the influence of salvianolic acid A (SAA) on the expression of CCL-20 in macrophages and ApoE-deficient (ApoE) mice.. The expression of CCL-20 was detected both at protein and messenger RNA levels in RAW264.7 cells. We validated the result in ApoE mice that were intraperitoneally injected with SAA. Phosphorylation of p38 mitogen-activated protein kinase was detected with Western blot, and inhibitor of p38 was used to investigate the mechanism of regulation of CCL-20. Hematoxylin and eosin and Oil-Red-O staining were used to evaluate the atherosclerotic lesions and lipid accumulation in ApoE mice. Immunohistochemical analysis was used to detect the expressions of CCL-20 and CCR6 in the atherosclerotic lesions. Immunofluorescent analysis was used to certify the origination of CCL-20.. Recombinant tumor necrosis factor-α (TNF-α) upregulated CCL-20 production in dose- and time-dependent manners in RAW264.7 cells. The activity of TNF-α-induced CCL-20 production seemed to be significantly suppressed by SAA. Using p38 mitogen-activated protein kinase inhibitor, we found that p38 mediated the effects of TNF-α- and SAA-induced CCL-20 expression changes. In addition, immunohistochemical analysis of aortic root of ApoE mice also demonstrated that the expressions of CCL-20 and CCR6 were both downregulated significantly with SAA treatment. Furthermore, treatment of SAA inhibited the progression of the atherosclerotic plaques and lipid accumulation.. These results demonstrate that TNF-α increased but SAA suppressed CCL-20 production significantly via a novel mechanism.

Topics: Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Blotting, Western; Caffeic Acids; Cell Line; Chemokine CCL20; Disease Models, Animal; Dose-Response Relationship, Drug; Lactates; Lipid Metabolism; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Sinus of Valsalva; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation