The High temperature requirement A (HtrA) proteases are a family of serine proteases conserved from bacteria to mammals, and are known to have important functions in protecting cells from stress conditions. There are four mammalian HtrA paralogs (HtrA1-4). HtrA1 is involved in apoptosis and anoikis, and is proposed to function as a tumour suppressor. It has also been implicated in the development of other diseases such as arthritis, Alzheimer’s disease, age-related macular degeneration, and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. We have previously shown that HtrA1 is highly enriched in the placenta compared to other tissues, and that in women HtrA1 is expressed in placental and endometrial cells at the placental-maternal interface during the first trimester of pregnancy.
HtrA1 has recently been reported to be upregulated in preeclampsia (PE), a pregnancy-specific systemic disorder primarily involving hypertension and proteinuria, typically occurring after 20 weeks of gestation in previously normotensive women. However, it is unclear whether HtrA1 is secreted into the maternal circulation and if serum HtrA1 is altered in preeclamptic pregnancies. In this study, we developed a specific sandwich enzyme linked immunosorbent assay (ELISA) suitable for the detection of serum HtrA1. Using this assay, we discovered that serum HtrA1 levels increase progressively throughout gestation in normal pregnancies. However, this trend was perturbed in women with PE. Compared to gestation-age matched normal pregnancies, HtrA1 serum levels are significantly increased in early-onset PE, which occurs before 34 weeks of gestation, but significantly reduced in late-onset PE, which occurs after 34 weeks of gestation.
This is the first report to show a clear increase of HtrA1 in the maternal circulation during normal pregnancy, consistent with HtrA1 being highly expressed in the placenta. This study also highlights the complex regulation of HtrA1 in different subsets of PE.