euscaphic-acid and Atherosclerosis

Tormentic acid (TA) is a triterpene isolated from the stem bark of the plant Vochysia divergens and has been reported to exhibit anticancer, anti‑inflammatory and anti‑atherogenic properties. However, the functions of TA in hydrogen peroxide (H2O2)‑induced oxidative stress and inflammation in rat vascular smooth muscle cells (RVSMCs) remain unclear. Therefore, the present study aimed to investigate whether TA suppressed H2O2‑induced oxidative stress and inflammation in RVSMCs, and to determine its molecular mechanisms. The present study demonstrated that TA inhibited reactive oxygen species (ROS) generation, induced H2O2 in RVSMCs, and inhibited H2O2-induced expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase (NOX) in RVSMCs. In addition, TA significantly decreased the production of tumor necrosis factor‑α (TNF‑α), interleukin 6 (IL‑6) and IL‑1β. Furthermore, TA pretreatment prevented nuclear factor‑κB (NF‑κB) subunit p65 phosphorylation and NF‑κB inhibitor α (IκBα) degradation induced by H2O2 in RVSMCs. TA is, therefore, suggested to inhibit H2O2-induced oxidative stress and inflammation in RVSMCs via inhibition of the NF‑κB signaling pathway. TA may have potential as a pharmacological agent in the prevention or treatment of atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Cell Survival; Cells, Cultured; Female; Hydrogen Peroxide; Inflammation; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Triterpenes

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.

Topics: Animals; Aorta; Atherosclerosis; Chemokine CCL2; Cholesterol; Diet, Atherogenic; Female; Male; Mice; Mice, Knockout; Receptors, LDL; Salvia; Structure-Activity Relationship; Triglycerides; Triterpenes; Xanthomatosis