Astragaloside IV ameliorates atherosclerosis by targeting TAK1 to suppress endothelial cell proinflammatory activation

Background: Atherosclerosis is a chronic inflammatory disease mainly characterized by the activation of endothelial cells and recruitment of macrophages, leading to plaque formation. Astragaloside IV (AS-IV), a natural saponin derived from Astragalus mongholicus Bunge, has been shown to confer protective effects against cardiovascular diseases. Purpose: The purpose of this study is to explore the role of AS-IV on atherosclerosis and the underlying mechanism. Methods: Mice with atherosclerosis were administered with AS-IV by oral gavage. Atherosclerotic plaques and blood lipid profiles of these mice were assessed. Endothelial cell activation and macrophage infiltration were examined by immunofluorescent or immunohistochemical staining. The effects of AS-IV on endothelial cell activation, macrophage migration and adhesion were determined by transwell experiments, RT-qPCR, and Western blot. Results: Mice treated with AS-IV exhibited a dose-dependent reduction in atherosclerotic plaque size, with no concomitant change in blood lipid levels. It significantly suppressed endothelial cell activation and macrophage infiltration in the vasculature. AS-IV inhibited TNF-alpha-induced endothelial cell activation and macrophage migration and adhesion in vitro. Furthermore, AS-IV reduced the phosphorylation of key kinases in the MAPK pathways and their upstream regulator TAK1 in endothelial cells. The inhibitory effects of AS-IV on MAPK pathways and endothelial cell activation were counteracted by TAK1 deficiency or overexpression of TAK1. Molecular docking analysis suggested AS-IV binds to TAK1 with high affinity. Conclusion: AS-IV exhibits anti-atherosclerotic effects by targeting TAK1 in endothelial cells, thereby inhibiting endothelial cell activation, and the subsequent adhesion and migration of macrophages, providing a prospective therapeutic strategy for the management of atherosclerosis.