Preeclampsia is a pregnancy-related disease with increasing maternal and perinatal morbidity and mortality worldwide. Defective trophoblast invasion is considered to be a major factor in the pathophysiological mechanism of
preeclampsia.
Heparanase, the only endo-β-
glucuronidase in mammalian cells, has been shown to be abnormally expressed in the placenta of
preeclampsia patients in our previous study. The biological role and potential mechanism of
heparanase in trophoblasts remain unclear. In the present study, stably transfected HTR8/SVneo cell lines with
heparanase overexpression or knockdown were constructed. The effect of
heparanase on cellular proliferation, apoptosis, invasion, tube formation, and potential pathways in trophoblasts was explored. Our results showed that overexpression of
heparanase promoted proliferation and invasion. Knockdown of
heparanase suppressed proliferation, invasion, and tube formation but induced apoptosis. These findings reveal that downregulation of
heparanase may contribute to defective placentation and plays a crucial role in the pathogenesis of
preeclampsia. Furthermore, increased activation of
p38 MAPK in
heparanase-knockdown HTR8/SVneo cell was shown by MAPK pathway phosphorylation array and Western blotting assay. After pretreatment with 3 specific
p38 MAPK inhibitors (
BMS582949,
SB203580, or
BIRB796), inadequate invasion in
heparanase-knockdown HTR8/SVneo cell was rescued. That indicates that knockdown of
heparanase decreases HTR8/SVneo cell invasion through excessive activation of the
p38 MAPK signaling pathway. Our study suggests that
heparanase can be a potential predictive
biomarker for
preeclampsia at an early stage of pregnancy and represents a promising therapeutic target for the treatment of
preeclampsia.