Oleanolic acid protects against pathogenesis of atherosclerosis, possibly via FXR-mediated angiotensin (Ang)-(1-7) upregulation

Abstract

Atherosclerosis, the leading cause of cardiovascular diseases in the world, is a chronic inflammatory disorder characterized by the dysfunction of arteries. Oleanolic acid (OA) is a bioactive nature product which exists in various plants and herbs. Previous studies have demonstrated that OA was involved in numerous of biological processes, including atherosclerosis. However, the exact mechanisms of the anti-atherosclerosis effects of OA remain unknown. Here, in our study, we analyzed the effects and possible underlying mechanisms of OA in atherosclerosis depending a cell model and an animal model of atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL, 100 μg/mL) for 24 h to establish an atherosclerotic cell model. New Zealand white (NZW) rabbits were fed with high-fat (HF) diets for three months to establish an atherosclerotic animal model. Then, cell viability and expression of cytokines (ANG, NO, eNOS, IL-1β, TNF-α, and IL-6) were measured with CCK-8 assay and ELISA kits, cell apoptosis and cell cycle distribution were analyzed by flow cytometry in the atherosclerotic cell model. Results showed that ox-LDL induced effects of anti-proliferation, cytokines alterations, and cell apoptosis were abolished by the application of OA or Ang (1-7). Further study indicated that OA increased the expression of ANG by upregulating the FXR expression in the ox-LDL induced HUVECs arthrosclerosis model. And the in vivo experiment in the HF diet induced animal model suggested that OA may inhibit the development of atherosclerosis. The atherosclerosis of aortas was assessed by Hematoxylin Eosin (HE), Oil Red O and Picrosirius Red staining; the expression levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were determined by the fully automatic biochemical analyzer, in the atherosclerotic animal model. All the results showed that OA treatment improved the cell viability in the cell model, inhibited the atherosclerosis development in the animal model. OA play as an anti-atherosclerosis agent in both the cell model and animal model by upregulating the production of Angiotensin (Ang)-(1-7) through FXR.

Keywords: Ang (1–7); Atherosclerosis; FXR; Oleanolic acid.