LAUSR

20(S)‐protopanaxadiol (PPD)‐type ginsenosides are generally believed to be the most pharmacologically active components of Panax ginseng. These compounds induce apoptotic cell death in various cancer cells, which suggests that they have anti‐cancer activity. Anti‐angiogenesis is a promising therapeutic approach for controlling angiogenesis‐related diseases such as malignant tumors, age‐related macular degeneration, and atherosclerosis. Studies showed that 20(S)‐PPD at low concentrations induces endothelial cell growth, but in our present study, we found 20(S)‐PPD at high concentrations inhibited cell growth and mediated apoptosis in human umbilical vein endothelial cells (HUVECs). The mechanism by which high concentrations of 20(S)‐PPD mediate endothelial cell apoptosis remains elusive. The present current study investigated how 20(S)‐PPD induces apoptosis in HUVECs for the first time. We found that caspase‐9 and its downstream caspase, caspase‐3, were cleaved into their active forms after 20(S)‐PPD treatment. Treatment with 20(S)‐PPD decreased the level of Bcl‐2 expression but did not change the level of Bax expression. 20(S)‐PPD induced endoplasmic reticulum stress in HUVECs and stimulated UPR signaling, initiated by protein kinase R‐like endoplasmic reticulum kinase (PERK) activation. Total protein expression and ATF4 nuclear import were increased, and CEBP‐homologous protein (CHOP) expression increased after treatment with 20(S)‐PPD. Furthermore, siRNA‐mediated knockdown of PERK or ATF4 inhibited the induction of CHOP expression and 20(s)‐PPD‐induced apoptosis. Collectively, our findings show that 20(S)‐PPD inhibits HUVEC growth by inducing apoptosis and that ATF4 expression activated by the PERK‐eIF2α signaling pathway is essential for this process. These findings suggest that high concentrations of 20(S)‐PPD could be used to treat angiogenesis‐related diseases.