ilexgenin-a and Atherosclerosis

Atherosclerosis (AS) is one of important events involving in the pathological process of coronary artery disease. Many traditional Chinese medicines have been widely used for the treatment of AS. Previous studies have demonstrated that Ilexgenin A (IA) obtained from Ilex hainanensis Merr. could improve AS development. However, its underlying mechanism is still unknown. This study was conducted to explore the possible targets and mechanisms involving in the anti-atheroclerosis effect of IA. The results showed IA significantly promoted NO production, reduced reactive oxygen species (ROS) generation, and inflammatory cytokine production induced by palmitate (PA) in endothelial cells, demonstrating IA could improve endothelial dysfunction. Meanwhile, IA dramatically inhibited dynamin-related protein 1 (Drp1) expression and mitochondrial fission induced by PA whereas proteasome inhibitor epoxomicin attenuated its effect on Drp1 expression, indicating IA decreased Drp1 expression with regulation of proteasome. Furthermore, IA also could increase the expression of proteasome subunit beta type5 (PSMB5) and activate nuclear factor-like 2 (Nrf2). Nrf2 knockdown eliminated the induction effect of IA on PSMB5 expression while abrogated its inhibition on ROS generation and mitochondrial fission stimulated by PA. These results demonstrated that IA could promote PSMB5 expression in an Nrf2-dependent manner, resulting in the suppression of mitochondrial fission, and thus improve endothelial dysfunction. These findings laid a foundation to the future development of IA as an agent to the prevention and treatment of AS.

Topics: Animals; Aorta; Atherosclerosis; Drugs, Chinese Herbal; Dynamins; Endothelial Cells; Gene Expression; Gene Knockdown Techniques; Male; Mitochondrial Dynamics; NF-E2-Related Factor 2; Proteasome Endopeptidase Complex; Rats, Sprague-Dawley; Triterpenes

Ilexgenin A (IA), a novel pentacyclic triterpenoid, is a compound extracted from leaves of Ilex hainanensis Merr. In this study, we explored the efficacy of IA on atherosclerosis and its underlying mechanism. We determined that treatment with IA attenuated atherosclerosis in high-fat diet-induced apolipoprotein E deficient mice via a series of effects involving regulation of lipid parameters, decrease of atherosclerosis-related indexes, inhibition of inflammatory cytokines secretion and pathological changes of main organs. Furthermore, the underlying mechanism of IA was investigated on oxidized low-density lipoprotein (Ox-LDL)-induced THP-1 cells. We showed that pre-treatment with IA decreased active inflammation cytokines involving interleukin-6 (IL-6), IL-1 and tumor necrosis factor-α (TNF-α) expression in a concentration-dependent manner. In addition, we confirmed that IA inhibited the phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), IKKα phosphorylation and NF-κB activity induced by Ox-LDL. Overall, these findings define IA as a novel drug candidate for anti-atherosclerotic therapy.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cell Line; Cytokines; Diet, High-Fat; Humans; I-kappa B Kinase; Lipid Metabolism; Lipoproteins, LDL; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Triterpenes