The neo-potential therapeutic strategy in preeclampsia: Downregulated miR-26a-2-3p motivates endothelial cell injury by targeting 15-LOX-1

Preeclampsia (PE) poses a life-threatening risk for both mothers and babies, and its onset and progression are linked to endothelial injury. The enzyme 15-lipoxygenase-1 (15-LOX-1), critical in arachidonic acid metabolism, is implicated in various diseases, yet its specific role and precise mechanisms in PE remain largely unknown. In this study, we found that 15-LOX-1 and its main metabolite, 15-HETE, were significantly increased in both the placenta and serum of PE patients. This increase was accompanied by elevated levels of endothelial injury markers, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). A positive correlation between 15-LOX-1 and those markers in the placenta. In Alox15(-/-) mice, Alox15 deficiency reduced endothelial cell injury in PE-like mice induced by L-NAME. In vitro studies showed that hypoxia-induced upregulation of 15-LOX-1 reduced the cell viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), while increasing apoptosis and inflammatory cell adhesion. Mechanistically, the p38 MAPK pathway was identified as a downstream target of 15-LOX-1. Knocking down 15-LOX-1 or inhibiting p38 MAPK activation improved endothelial cell injury in hypoxia-treated HUVECs. Furthermore, downregulation of miR-26a-2-3p was found to correlate negatively and colocalize with 15-LOX-1 upregulation in the placenta of PE patients. Luciferase reporter assays further confirmed that miR-26a-2-3p directly bind to the 3 ' UTR of 15-LOX-1, targeting its expression. Moreover, miR-26a-2-3p agomir ameliorated the PE-like phenotype in mice through the 15-LOX-1/p38 MAPK axis, improving endothelial dysfunction. Therefore, our study provides novel insights into the pathogenesis of PE and highlight modulating the miR-26a-2-3p/15-LOX-1/p38 MAPK axis as a potential therapeutic target for PE.