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Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.

ABSTRACT: Vascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling. Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype. Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC. In addition, the loss of HTRA1 enhanced TGF?-SMAD2/3 signaling activity. Activation of either NOTCH3 or TGF? signaling resulted in increased transcription of the HES and HEY transcriptional repressors and promoted the contractile VSMC phenotype. However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes. As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice. These data demonstrate an essential role of HTRA1 in vascular maturation and homeostasis by controlling Notch and TGF? signaling.

SUBMITTER: Klose R

PROVIDER: S-EPMC6890777 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.

Klose Ralph R Prinz Alexander A Tetzlaff Fabian F Weis Eva-Maria EM Moll Iris I Rodriguez-Vita Juan J Oka Chio C Korff Thomas T Fischer Andreas A

Scientific reports 20191203 1

Vascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling. Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype. Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH ...[more]

PMID: 31796853

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Project description:HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p?=?0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR?=?0.45 [CI 0.23-0.90], p?=?0.023; HR?=?0.55 [CI 0.32-0.94], p?=?0.028, respectively), with even more pronounced impact in node-positive patients (HR?=?0.21 [CI 0.07-0.63], p?=?0.006; HR?=?0.29 [CI 0.13-0.65], p?=?0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n?=?2809): HR?=?0.79 [CI 0.7-0.9], log-rank p?=?0.0003; for OS (n?=?971): HR?=?0.63 [CI 0.48-0.83], log-rank p?=?0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.

Dataset Information

Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.

Publications

Loss of the serine protease HTRA1 impairs smooth muscle cells maturation.

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