Low Serum Levels of HtrA3 at 15 Weeks of Gestation Are Associated with Late-Onset Preeclampsia Development and Small for Gestational Age Birth

Teoh, Sonia Soo Yee; Wang, Yao; Liu, Ying; Leemaqz, Shalem; Dekker, Gus; Roberts, Claire T.; Nie, Guiying

doi:10.1159/000497144

Cited by 6 publications

(3 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other potential factors that may improve the prediction of late-onset pre-eclampsia but which require validation in large cohorts or meta-analyses include second-trimester circulating HtrA3 (ref. 259 ), cell-free RNA 260,261 , and third-trimester circulating ELABELA 262 and progranulin 263 .…”

Section: Screeningmentioning

confidence: 99%

Pre-eclampsia

Dimitriadis

Rolnik

Zhou

et al. 2023

Nat Rev Dis Primers

127

View full text Add to dashboard Cite

Pre-eclampsia is a life-threatening disease of pregnancy unique to humans and a leading cause of maternal and neonatal morbidity and mortality. Women who survive pre-eclampsia have reduced life expectancy, with increased risks of stroke, cardiovascular disease and diabetes, while babies from a pre-eclamptic pregnancy have increased risks of preterm birth, perinatal death and neurodevelopmental disability and cardiovascular and metabolic disease later in life. Preeclampsia is a complex multisystem disease, diagnosed by sudden-onset hypertension (>20 weeks of gestation) and at least one other associated complication, including proteinuria, maternal organ dysfunction or uteroplacental dysfunction. Pre-eclampsia is found only when a placenta is or was recently present and is classified as preterm (delivery <37 weeks of gestation), term (delivery ≥37 weeks of gestation) and postpartum pre-eclampsia. The maternal syndrome of pre-eclampsia is driven by a dysfunctional placenta, which releases factors into maternal blood causing systemic inflammation and widespread maternal endothelial dysfunction. Available treatments target maternal hypertension and seizures, but the only 'cure' for pre-eclampsia is delivery of the dysfunctional placenta and baby, often prematurely. Despite decades of research, the aetiology of pre-eclampsia, particularly of term and postpartum pre-eclampsia, remains poorly defined. Significant advances have been made in the prediction and prevention of preterm pre-eclampsia, which is predicted in early pregnancy through combined screening and is prevented with daily low-dose aspirin, starting before 16 weeks of gestation. By contrast, the prediction of term and postpartum pre-eclampsia is limited and there are no preventive treatments. Future research must investigate the pathogenesis of pre-eclampsia, in particular of term and postpartum pre-eclampsia, and evaluate new Nature Reviews Disease Primers | (2023) 9:8 2 0123456789();: Primer Epidemiology Incidence and mortalityThe global prevalence of all pre-eclampsia in the years 2002-2010 was estimated at 4.6% of deliveries but reported regional rates varied between 1% and 5.6% 14 . Where reported, the prevalence of preterm pre-eclampsia is <1% [15][16][17][18] . The prevalence of pre-eclampsia is generally reported as lower in low-income and middle-income countries (LMICs) (except sub-Saharan Africa) than in high-income countries (HICs) 19,20 ; however, it is likely that differences in classification, access to prenatal care and under-reporting in LMICs affect prevalence data 20,21 . Furthermore, most pre-eclampsia research is performed in HICs, potentially leading to bias and generalizability concerns in the populations sampled and the research questions asked.Hypertensive disorders of pregnancy (including pre-eclampsia) are the second most common cause (behind haemorrhage) of maternal Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rights...

show abstract

Section: Screeningmentioning

confidence: 99%

Pre-eclampsia

Dimitriadis

Rolnik

Zhou

et al. 2023

Nat Rev Dis Primers

127

View full text Add to dashboard Cite

show abstract

“…Women who are destined to develop preeclampsia have significantly higher levels of serum HtrA3 at 13–14 weeks of gestation, well before clinical symptoms manifest [ 22 , 73 ]. Furthermore, serum levels of HtrA3 at 11–13 weeks as well as at 15 weeks of gestation are significantly lower in pregnancies that proceed with subsequent intrauterine growth restriction (IUGR) [ 128 , 129 ]. These studies collectively suggest that an optimal concentration of HtrA3 during early pregnancy is necessary for the development of a functional placenta, and that HtrA3 may be a potentially useful biomarker for the early diagnosis/prediction of preeclampsia and IUGR [ 130 ].…”

Section: Htras In Placental Development and Pregnancy Complicationsmentioning

confidence: 99%

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications

Wang

Nie

2021

IJMS

Self Cite

View full text Add to dashboard Cite

The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.

show abstract

“…HtrA3, first identified as a pregnancy-related serine protease (PRSP), plays an important role in regulating trophoblast invasion during placentation [10,[34][35][36][37]. Research in the past few years has linked this protein to cancer development due to its involvement in apoptosis and cell signaling and it has recently emerged as a potential tumor suppressor [33].…”

Section: Introductionmentioning

confidence: 99%

A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3

Acharya

Dutta

Bose

2020

Biochemical Journal

View full text Add to dashboard Cite

Human HtrA3 (high-temperature requirement protease A3) is a trimeric multitasking propapoptotic serine protease associated with critical cellular functions and pathogenicity. Implicated in diseases including cancer and pre-eclampsia, its role as a tumor suppressor and potential therapeutic target cannot be ignored. Therefore, elucidating its mode of activation and regulatory switch becomes indispensable towards modulating its functions with desired effects for disease intervention. Using computational, biochemical and biophysical tools, we delineated the role of all domains, their combinations and the critical phenylalanine residues in regulating HtrA3 activity, oligomerization and specificity. Our findings underline the crucial roles of the N-terminus as well as the PDZ domain in oligomerization and formation of a catalytically competent enzyme, thus providing new insights into its structure–function coordination. Our study also reports an intricate ligand-induced allosteric switch, which redefines the existing hypothesis of HtrA3 activation besides opening up avenues for modulating protease activity favorably through suitable effector molecules.

show abstract

Low Serum Levels of HtrA3 at 15 Weeks of Gestation Are Associated with Late-Onset Preeclampsia Development and Small for Gestational Age Birth

Cited by 6 publications

References 41 publications

Pre-eclampsia

Pre-eclampsia

Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications

A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3

Contact Info

Product

Resources

About