Gadd45a knockdown alleviates oxidative stress through suppressing the p38 MAPK signaling pathway in the pathogenesis of preeclampsia.

OBJECTIVE: Preeclampsia (PE) is a hypertensive disease associated with vascular oxidative stress (OS). Besides, cell response to OS triggers growth arrest and DNA damage inducible alpha (Gadd45a). Herein, we investigated the effect of Gadd45a on OS in PE.

METHODS: Umbilical cord tissues and peripheral blood samples were collected from PE patients and normal pregnant women. Immunohistochemistry was applied to identify Gadd45a level and extent of p38 phosphorylation. To verify the effect of Gadd45a on CRL1730 human umbilical vein endothelial cell (HUVEC) behavior, HUVECs were treated with hypoxia/reoxygenation (H/R) and Gadd45a-siRNA or P79350. OS products were detected using thiobarbituric acid-reactive-substance assay, immune enzyme assay, enzyme-linked immunosorbent assay (ELISA) and super oxide dismutase (SOD) kit. HUVEC behaviors were evaluated using flow cytometry, wound-healing test, and Transwell assay. The tube formation ability was assessed using in vitro tube formation assay.

RESULTS: PE umbilical cord tissues exhibited increased Gadd45a expression, extent of p38 phosphorylation, 8-isoprostane and oxidatively modified low density lipoprotein (Ox-LDL) and decreased SOD levels. HUVECs treated with H/R or agonist + H/R showed similar expression tendencies of related genes, enhanced apoptosis and inhibited migration, invasion, and blood vessel formation. Gadd45a-siRNA conferred alleviation to OS with decreased apoptosis, greater cell migration, invasion and blood vessel, which appeared to be weakened by treatment of Gadd45a siRNA + P79350.

CONCLUSION: Over-expression of Gadd45a and activation of the p38 MAPK signaling pathway are associated with OS in PE. Furthermore, Gadd45a knockdown promotes cell migration and invasion, and the tube formation, thus alleviating OS in PE.