Mechanism Of Geniposide Inhibiting Macrophage-derived Foam Cell Formation

Atherosclerosis（AS）is a chronic inflammatory disease in which cholesterol-rich macrophages accumulate on the arterial wall,causing imbalance in lipid metabolism and adaptive immune response.The formation of macrophage-derived foam cells is a key step in atherosclerosis and an early sign of atherosclerosis.Geniposide（Gen）is one of the main medicinal components of Rubiaceae plant gardeniae.Studies have found that it has anti-atherosclerotic effects,but its mechanism is unclear.In this research,we mainly investigated whether geniposide can exert its protective effect on atherosclerosis by inhibiting the formation of foam cells,and clarified its possible molecular mechanism.Here,Lysophosphatidic Acid（LPA）was used to induce the foaming of Raw264.7 macrophages to establish a stable macrophage-derived foam cell model.CCk-8 was used to detect the effects of different concentrations of geniposide on Raw264.7 macrophages.The total cholesterol detection kit and oil red O staining were used to compare the inhibition of macrophage-derived foam cells formation before and after geniposide treatment.WB and RT-PCR were used to detect lipid transport-related proteins and mRNA levels and to further explore their possible mechanisms.Meanwhile,ApoE^-/-mice were fed with a high-fat diet for 16 weeks to establish an atherosclerosis model of ApoE^-/-mice.After treating ApoE-/-mice with different doses of geniposide in the last four weeks,the effect of geniposide on atherosclerosis in ApoE^-/-mice was evaluated by oil red O staining and hematoxylin-eosin staining.The serum-related indicators of ApoE^-/-mice were detected by a biochemical analyzer.And WB and immunohistochemical techniques were used to verify the mechanism of geniposide inhibiting atherosclerosis in ApoE^-/-mice.Research shows that:（1）Geniposide inhibits the formation of macrophage-derived foam cells in a dose-dependent manner;（2）In Raw264.7 macrophages,geniposide up-regulates ABCA1 and SR-B1 and down-regulates SR-A expression;（3）Compared with the blank control,geniposide significantly reduced serum TC、TG and LDL-C levels in ApoE^-/-mice,while geniposide was dose-dependent Inhibits the development of atherosclerosis in ApoE^-/-mice;（4）Geniposide can down-regulate the mRNA and protein levels of SR-A by inhibiting p38MAPK and AKT signaling pathways,and Up-regulate ABCA1/SR-B1mRNA and protein levels.Protein levels significantly inhibited the formation of macrophage-derived foam cells.In summary,our research shows that geniposide can exert anti-atherosclerotic effects by regulating the balance of the expression of various lipid transporters in cell membranes associated with p38MAPK and AKT signaling pathways,and further inhibiting the formation of foam cells.The results showed that gardenoside was a potential drug for the treatment of atherosclerosis.