Ursane triterpenoids inhibit atherosclerosis and xanthoma in LDL receptor knockout mice

In order to determine the mechanism of triterpenes, a class of secondary metabolites in plants, in modulating progression of vascular atherosclerotic lesions, we isolated three ursane triterpenoids (euscaphic acid, tormentic acid and 2alpha-hydroxyursolic acid) from aerial part of Salvia miltirrhiza Bge. and fed LDLr(-/-) mice the isolated compounds at a dose of 10 mg/kg p.o. for 24 weeks.

The treated mice were raised with a cholesterol-enriched (1.25%) diet. Implying serum and aorta MCP-1 analysis, we found that all mice treated with the compounds exhibited a significant reduction of whole body and vascular inflammation.

The reduction of macrophage cells' number in aortic atherosclerotic lesions suggests that triterpenes treatment results in the development of a more stable plaque phenotype. Analysis of the structure-activity relationships demonstrates that compounds with a beta-orientated hydrogen-bond forming group at C-3 exhibit more potent anti-atherogenic effect than the alpha-counterpart on the development of atherosclerosis and xanthoma. However, the biological activities of the compounds are significantly reduced when they have C-19 hydrogen-bonds.

These Results suggest that down-regulation of MCP-1 is the main mechanism for antiatherogenic activity of triterpenes and MCP-1 might play important roles in the development of atherosclerosis and xanthoma.