Geniposide alleviates atherosclerosis by regulating macrophage polarization via the FOS/MAPK signaling pathway

To assess geniposide's effects in New Zealand rabbits with high-fat diet induced atherosclerosis and to explore the underpinning mechanisms. Aorta histological changes were evaluated by intravenous ultrasound (IVUS) and H&E staining. Lipid accumulation in the aortic was quantified by Oil Red O staining. Then, RNA sequencing (RNA-seq) was carried out for detecting differentially expressed genes in rabbit high-fat diet induced atherosclerosis. The levels of the cytokines CRP, IL-1β and IL-10 were determined by ELISA. Protein levels of iNOS and Arg-1 were assessed by Western blot and immunohistochemical staining. The mRNA expression levels of NR4A1, CD14, FOS, IL1A, iNOS and Arg-1 were detected by quantitative real-time PCR (qPCR). Geniposide markedly reduced the degree of atherosclerotic lesions in aorta tissues. RNA-seq and qPCR demonstrated that NR4A1, CD14, FOS and IL1A mRNA amounts were overtly increased in New Zealand rabbits with high-fat diet induced atherosclerosis. Moreover, geniposide reduced iNOS (M1 phenotype) mRNA and protein amounts as well as IL-1β secretion, which were enhanced in New Zealand rabbits with high-fat diet induced atherosclerosis. Besides, Arg-1 (M2 phenotype) mRNA and protein amounts were significantly increased after geniposide treatment, as well as IL-10 secretion. These findings suggest that geniposide could inhibit the progression of and stabilize atherosclerotic plaques in rabbits by suppressing M1 macrophage polarization and promoting M2 polarization through the FOS/MAPK signaling pathway.