The roles of metformin and pravastatin on placental endoplasmic reticulum stress and placental growth factor in human villous-Like trophoblastic BeWo cells

Abstract

Preeclampsia (PE) is related to an imbalance of angiogenic factors. Placental growth factor (PlGF) is reduced in early onset PE. Recent evidence indicates that metformin and statins may suppress endoplasmic reticulum (ER) stress. We previously reported that the unfolded protein response activated by ER stress down-regulated PlGF protein expression and predicted these drugs could prevent placental ER stress and up-regulate PlGF protein expression in trophoblast-like cells. In this study, we aimed to establish the effects of these drugs on PlGF and activating transcription factor 4 (ATF4) protein expression. We confirmed that PlGF messenger RNA (mRNA) levels were decreased under ER stress induced by thapsigargin and that ATF4 mRNA was increased under the same conditions and then administered metformin to it. Transcript analysis showed increased PlGF mRNA compared with thapsigargin only treatment and that this was dependent on metformin levels. Under ER stress, western blot showed high levels of ATF4 and phosphorylated-eukaryotic initiation factor 2 subunit α (p-eIF2α) but low levels of PlGF protein. By contrast, compared with thapsigargin alone, ATF4 and p-eIF2α levels were low and PlGF levels were high when metformin and thapsigargin were given, but these were again dependent on metformin concentrations. Western blot also confirmed that pravastatin attenuated ER stress and increased PlGF protein expression. In conclusion, metformin and pravastatin suppressed ER stress and restored PlGF levels in trophoblast-like cells. However, although these results indicate that these drugs have a potential for preventing or treating PE, the lack of clarity on the mechanism requires further study