Upregulation of HtrA4 in the placentas of patients with severe pre-eclampsia.

High temperature requirement A (HtrA) family proteins are serine proteases that may serve in the quality control of misfolded or mislocalized proteins. Recently, possible involvements of HtrA1 in the normal development of the placenta and in the pathogenesis of pre-eclampsia were reported. In this study, we characterized HtrA4, a previously uncharacterized HtrA protein family member, in pre-eclampsia. Elevated expression levels of placental HtrA4 in pre-eclampsia patients were observed by qRT-PCR. Western blotting also showed an increased production of HtrA4 at the protein level in pre-eclamptic placentas. In normal chorionic villi, HtrA4 protein was more abundant in the cytoplasm of cytotrophoblasts than in syncytiotrophoblasts. In contrast, the amount of HtrA4 protein in syncytiotrophoblasts was dramatically increased in pre-eclamptic placentas. Circulating HtrA4 was detected at higher levels in sera from women with pre-eclampsia than from those with normotensive pregnancies. Serum HtrA4 levels were higher in patients with early onset and inversely correlated with the weights of the newborn and placenta. Furthermore, serum levels correlated with serum PAPP-A and PAPP-A2 levels, indicating a functional role for HtrA4 in the common pathway. These data suggest that increased HtrA4 may be involved in the onset of pre-eclampsia, and elevated levels in sera imply a potential application as a biomarker for this disorder.