Abstract

BACKGROUND Atherosclerosis is a leading cause of mortality worldwide. The gut microbiota (GM) plays a significant role in the initiation and progression of atherosclerosis, making its modulation a promising therapeutic strategy for atherosclerotic cardiovascular disease. Salvia miltiorrhiza, a traditional Chinese medicine renowned for its therapeutic effects in treating cardiovascular diseases, contains lithospermic acid (LA) as one of its key active constituents. PURPOSE To elucidate whether LA can alleviate atherosclerosis and its mechanism. STUDY DESIGN AND METHODS Atherosclerosis was induced in Apolipoprotein E knockout mice through a Western diet, followed by a 12-week treatment with LA. In a separate model, low-density lipoprotein receptor knockout mice were fed a Western diet for 8 weeks prior to receiving LA for an additional 12 weeks. The role of GM in LA-mediated alleviation of atherosclerosis was assessed using fecal microbiota transplantation (FMT) models coupled with 16S rRNA gene sequencing. Furthermore, serum metabolomics was employed to elucidate the mechanism by which LA modulates serum metabolites via GM to attenuate atherosclerosis. RESULTS LA administration significantly attenuated the development of atherosclerosis in both models. FMT experiments further indicated that the GM contributes to the anti-atherosclerotic effects of LA. 16S rRNA gene sequencing revealed that LA modified the composition of the GM. Metabolomic analysis demonstrated that LA reduced serum levels of lysophosphatidylcholine (LysoPC), a metabolite critical for macrophage function. CONCLUSION Collectively, these findings highlight the therapeutic potential of LA in the treatment of atherosclerosis.