Human HtrA4 Expression Is Restricted to the Placenta, Is Significantly Up-Regulated in Early-Onset Preeclampsia, and High Levels of HtrA4 Cause Endothelial Dysfunction

Singh, Harmeet; Zhao, Min; Chen, Qi; Wang, Yao; Liu, Ying; Kaitu’u-Lino, Tu’uhevaha J; Tong, Stephen; Nie, Guiying

doi:10.1210/jc.2014-3969

Cited by 46 publications

(68 citation statements)

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“…Thus, it is possible that HtrA1/3 may function antagonistically to HtrA4 during embryo implantation. During normal pregnancy the HtrA4 expression level changes and its aberrations have been correlated with preeclampsia [88,90]. HtrA4 may also, like HtrA1/3, modulate the ECM proteins e it has already been shown that it cleaves fibronectin in vitro [89].…”

Section: Human Htra Proteins In Cellular Physiology and Pathogenesismentioning

confidence: 99%

Structural insights into the activation mechanisms of human HtrA serine proteases

Żurawa-Janicka

Wenta

Jarzab

et al. 2017

Archives of Biochemistry and Biophysics

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Section: Human Htra Proteins In Cellular Physiology and Pathogenesismentioning

confidence: 99%

Structural insights into the activation mechanisms of human HtrA serine proteases

Żurawa-Janicka

Wenta

Jarzab

et al. 2017

Archives of Biochemistry and Biophysics

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“…We have recently reported that high temperature requirement A4 (HtrA4) is a placenta-specific protease that is significantly increased in the circulation of early-onset PE [23]. HtrA4 belongs to a serine protease family that also includes HtrA1, HtrA2 and HtrA3.…”

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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“…In humans, HTRA participates in the regulation of cell death, cell signalling and motility, apoptosis, and other processes [Singh et al, 2015]. Interestingly, in a fusion with Rv1196 protein, an M. tuberculosis HtrA (called Rv0125) has shown to enhance the protection conferred by BCG in M. tuberculosis -infected guinea pigs [Brandt et al, 2004].…”

Section: Resultsmentioning

confidence: 99%

ERAP1 and PDE8A Are Downregulated in Cattle Protected against Bovine Tuberculosis

et al. 2017

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Bovine tuberculosis (bTB) is a zoonotic disease caused by Mycobacterium bovis that is responsible for significant economic losses worldwide. In spite of its relevance, the limited knowledge about the host immune responses that provide effective protection against the disease has long hampered the development of an effective vaccine. The identification of host proteins with an expression that correlates with protection against bTB would contribute to the understanding of the cattle defence mechanisms against M. bovis infection. In this study, we found that ERAP1 and PDE8A were downregulated in vaccinated cattle that were protected from experimental M. bovis challenge. Remarkably, both genes encode proteins that have been negatively associated with immune protection against bTB.

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Human HtrA4 Expression Is Restricted to the Placenta, Is Significantly Up-Regulated in Early-Onset Preeclampsia, and High Levels of HtrA4 Cause Endothelial Dysfunction

Abstract: HtrA4 represents a novel placenta-specific serine protease that is altered specifically in early-onset PE with potential causal roles in endothelial dysfunction and disease development.

Cited by 46 publications

References 50 publications

Structural insights into the activation mechanisms of human HtrA serine proteases

Structural insights into the activation mechanisms of human HtrA serine proteases

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

<b><i>ERAP1</i></b> and <b><i>PDE8A</i></b> Are Downregulated in Cattle Protected against Bovine Tuberculosis

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