Downregulated PSME3 Contributes to Severe Preeclampsia by Promoting Trophoblast Cell Apoptosis

Severe preeclampsia (sPE) is a serious condition posing risks to both maternal and fetal health. Based on mass spectrometry analysis, we identified a key protein, PSME3 (proteasome activator subunit 3), an 11S proteasome activator, whose protein level was significantly downregulated in sPE placentas and whose function in sPE remains unknown.

PSME3 protein levels in human placental tissue were detected using Western blot, and PSME3 concentration in serum was detected by ELISA assay. The human preeclampsia-like phenotypes of Psme3^-/- pregnant mice were examined. Trophoblast cell apoptosis was detected by flow cytometry. Pregnant mice were treated with 9.5% O₂ to construct a preeclampsia mouse model for detecting placental Psme3 expression. The regulation of PSME3 expression by hypoxia was detected in trophoblast cell lines treated with 21% O₂ or 1% O₂.

PSME3 protein levels were significantly downregulated in sPE placentas and serum. Pregnant mice with Psme3^-/- embryos and placentas spontaneously presented human preeclampsia-like symptoms, including hypertension and proteinuria, increased serum soluble fms-like tyrosine kinase 1 concentration, fetal growth restriction, and increased cellular apoptosis. Mechanically, PSME3 knockdown promoted the apoptosis of trophoblast cells by repressing the degradation of UBE2V2 (ubiquitin conjugating enzyme E2 V2). Moreover, the placentas of hypoxia-induced preeclampsia mice presented significantly reduced Psme3 protein levels and elevated Ube2v2 protein levels. Hypoxia-inducible factor-1α functioned as a transcriptional repressor of PSME3.

In sPE placentas, hypoxia of the placenta may lead to the transcriptional inhibition of PSME3. PSME3 deficiency promotes the accumulation of UBE2V2, thereby inducing trophoblast cell apoptosis. Our study provides a new perspective for elucidating the pathogenesis of sPE.