ANGPTL4 mediates the protective role of PPAR. activators in the pathogenesis of preeclampsia

Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to be a therapeutic target for preeclampsia (PE). Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional secretory protein involved in regulating lipid metabolism and angiogenesis in various tissues. However, the expression of PPAR gamma and ANGPTL4 and their interaction in PE remain elusive. Here we showed that PPAR gamma agonist rosiglitazone upregulated the expression and secretion of ANGPTL4 in a dose-dependent manner in HTR8/SVneo cells, human umbilical vein endothelial cells (HUVECs) and placental explants. More importantly, we confirmed that the PPAR gamma/retinoid X receptor alpha heterodimer specifically binds to the ANGPTL4 promoter region and enhances its transcriptional activity. In addition, the levels of ANGPTL4 and PPAR gamma activators in the serum and their expression in placental tissues were significantly reduced in preeclamptic patients compared with normal pregnant subjects. Furthermore, functional studies demonstrated that ANGPTL4 mediates the facilitative effects of the PPAR gamma agonist on the survival, proliferation, migration and invasion of HTR8/SVneo cells, placental explants outgrowth and angiogenesis in HUVECs. Taken together, our results suggest that ANGPTL4 is a potential target gene for PPAR gamma and mediates the protective role of PPAR gamma activators in the pathogenesis of PE.