Effect of betulinic acid on high glucose‐induced vascular smooth muscle cells proliferation

Abstract

Betulinic acid (BA) is a pentacyclic triterpene found in Lycopus lucidus Turcz. Hyperglycemia has been shown to stimulate vascular smooth muscle cells proliferation, a paramount feature in atherosclerosis. The aim of this study was to determine the effects of BA on high glucose‐induced human aortic smooth muscle cell (HASMC) proliferation. In this study, [3H]‐thymidine incorporation under 25 mM glucose (HG) was significantly accelerated compared with 5.5 mM glucose and this increase was inhibited by BA. Invasion and migration assay also suggested an anti‐proliferative effect of BA. BA elevated the protein content of p21waf1/cip1, p27kip1, decreased cyclin D1/E and CDK2/4, suggesting that BA inhibited HASMC proliferation by regulating the cell progression from G1 to S phase. We showed that BA significantly inhibited HG‐induced matrix metalloproteinase (MMP)‐2/‐9 activity in a dose‐dependent manner. BA inhibited the HG‐induced hydrogen peroxide production and DCF‐sensitive intracellular ROS formation. Furthermore, BA suppressed the translocation and promoter transcriptional activity of NF‐κB under HG condition. BA also decreased HG‐induced phosphorylation of IκB‐α. In conclusion, the present data suggested that BA regulated cell cycle regulatory proteins, and significantly reduced HASMC proliferation, via inhibition of ROS and NF‐κB activation in hyperglycemia conditions.