Serum HtrA1 is differentially regulated between early-onset and late-onset preeclampsia

Teoh, Sonia Soo Yee; Zhao, Min; Wang, Yao; Chen, Qi; Nie, Guiying

doi:10.1016/j.placenta.2015.07.001

Cited by 34 publications

(29 citation statements)

References 44 publications

(37 reference statements)

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“…Placental HtrA1 expression is significantly increased in PE, especially in the early-onset PE subtype [9,[31][32][33]. We have further reported that placental HtrA1 protein is secreted into the maternal circulation, and that the circulating levels of HtrA1 are also significantly elevated in early-onset PE compared to gestationaged-matched controls [10].…”

Section: Introductionsupporting

confidence: 58%

“…HtrA1 is expressed ubiquitously, but the highest level is found in the placenta [2,3]. To date, dysregulation of HtrA1 has been implicated in a number of diseases such as cancer [4,5], arthritis [6], age-related macular degeneration (AMD) [7], neurodegenerative and neuromuscular disorders [8], and pregnancy complication preeclampsia [9,10]. Intriguingly, while HtrA1 is down-regulated in a number of cancers [4,5,11,12], it is up-regulated in AMD [7,13,14] and preeclampsia (PE) [9,10].…”

Section: Introductionmentioning

confidence: 99%

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HtrA1 alters endothelial tube formation characteristics in an in vitro model

Singh

Nie

2019

Preprint

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High temperature requirement factor A1 (HtrA1) is a serine protease of the mammalian HtrA family. It is ubiquitously expressed with high levels in the placenta. Dysregulation of HtrA1 has been linked to a number of diseases, in particular age-related macular degeneration (AMD) and preeclampsia (PE) in which HtrA1 is significantly increased.AMD is the leading cause of irreversible visual impairment in older people, affecting millions across the globe. PE is a life-threatening pregnancy complication, affecting 2-7% of pregnant women worldwide. Although AMD and PE are very different diseases, both are associated with endothelial dysfunction and dysregulation of angiogenesis.Given HtrA1 is up-regulated in both AMD and PE, in this study we examined the impact of excessive HtrA1 on capillary tube formation of HUVECs as an in vitro angiogenesis model. HtrA1 at high concentrations significantly increased the total number of tube branch points and inter-tubular loops, but considerably decreased the mean tube length, resulting in more but much smaller tubes. However, these smaller tubes were incomplete/broken. These data demonstrated that high concentrations of HtrA1 altered endothelial tube formation characteristics of HUVEVs. Our results suggest that HtrA1 over-expression in AMD and PE may directly contribute to the endothelial dysfunction in these diseases.

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Section: Introductionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

HtrA1 alters endothelial tube formation characteristics in an in vitro model

Singh

Nie

2019

Preprint

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“…bone sialoprotein, fibronectin, elastin, fibromodulin, TGF-β1) [15–19] proteins. Subsequently, interest in HTRA1’s contribution to human development and disease is wide ranging, encompassing numerous research fields such as cancer [20, 21], reproduction [22, 23], neurology [17, 24], and the musculoskeletal system [25]. …”

Section: Introductionmentioning

confidence: 99%

Role of HTRA1 in bone formation and regeneration: In vitro and in vivo evaluation

et al. 2017

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The role of mammalian high temperature requirement protease A1 (HTRA1) in somatic stem cell differentiation and mineralized matrix formation remains controversial, having been demonstrated to impart either anti- or pro-osteogenic effects, depending on the in vitro cell model used. The aim of this study was therefore to further evaluate the role of HTRA1 in regulating the differentiation potential and lineage commitment of murine mesenchymal stem cells in vitro, and to assess its influence on bone structure and regeneration in vivo. Our results demonstrated that short hairpin RNA-mediated ablation of Htra1 in the murine mesenchymal cell line C3H10T1/2 increased the expression of several osteogenic gene markers, and significantly enhanced matrix mineralization in response to BMP-2 stimulation. These effects were concomitant with decreases in the expression of chondrogenic gene markers, and increases in adipogenic gene expression and lipid accrual. Despite the profound effects of loss-of-function of HTRA1 on this in vitro osteochondral model, these were not reproduced in vivo, where bone microarchitecture and regeneration in 16-week-old Htra1-knockout mice remained unaltered as compared to wild-type controls. By comparison, analysis of femurs from 52-week-old mice revealed that bone structure was better preserved in Htra1-knockout mice than age-matched wild-type controls. These findings therefore provide additional insights into the role played by HTRA1 in regulating mesenchymal stem cell differentiation, and offer opportunities for improving our understanding of how this multifunctional protease may act to influence bone quality.

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“…Emerging evidence strongly suggests that the two PE subtypes have vastly different etiologies, and early-onset PE poses a far more significant maternal risk, with a 20-fold higher mortality rate than late-onset PE [16], [17], [18], [19]. The risk of cardiovascular disease is also much higher in women who have had early-onset than late-onset PE [20], [21], [22], suggesting that endothelial injury is more profound in early-onset than late-onset PE.…”

Section: Introductionmentioning

confidence: 99%

High levels of HtrA4 observed in preeclamptic circulation drastically alter endothelial gene expression and induce inflammation in human umbilical vein endothelial cells

Wang

Nie

2016

Placenta

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IntroductionPreeclampsia (PE) is a life-threatening pregnancy disorder characterized by wide-spread endothelial dysfunction. Placental factors circulating in the maternal blood are believed to cause endothelial dysfunction. Our previous study identified HtrA4 as a placenta-specific serine protease that is released into the maternal circulation and significantly increased in early-onset PE. In this study, we examined the impact of HtrA4 on expression of endothelial genes related to vessel biology, using human umbilical vein endothelial cells (HUVECs) as a model.MethodsHUVECs were treated with 0 or 3 μg/ml HtrA4 (highest concentration seen in PE circulation) for 24 h and analysed by an endothelial cell biology PCR array containing 84 genes. HtrA4-induced changes were then validated by real-time RT-PCR and ELISA for time and dose dependency.ResultsHigh levels of HtrA4 significantly altered the expression of a range of genes related to inflammation, vaso-activity, angiogenesis, cell adhesion, platelet activation and coagulation. In particular, pro-inflammatory genes IL6, PTGS2 (COX2) and IL1B were significantly increased by HtrA4. IL6 protein in HUVEC media was also drastically increased. THBD, an anticoagulant factor reported to be increased in PE, was significantly up-regulated by HtrA4. In contrast, THBS1, which is involved in many regulatory processes of endothelial cell biology, was severely down-regulated by HtrA4.DiscussionHtrA4 significantly increased the inflammatory responses of HUVECs, and altered their expression of a number of genes important for vessel biology. These data suggest that placenta-derived HtrA4 that is increased in PE circulation is a potential causal factor of endothelial dysfunction.

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Serum HtrA1 is differentially regulated between early-onset and late-onset preeclampsia

Cited by 34 publications

References 44 publications

HtrA1 alters endothelial tube formation characteristics in an in vitro model

HtrA1 alters endothelial tube formation characteristics in an in vitro model

Role of HTRA1 in bone formation and regeneration: In vitro and in vivo evaluation

High levels of HtrA4 observed in preeclamptic circulation drastically alter endothelial gene expression and induce inflammation in human umbilical vein endothelial cells

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