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Published on: August 14, 2017
Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and
Kristina Byskov1, Thomas Boettger2, Paul F Ruehle3
1Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Background And Aims:
The factor VII activating protease (FSAP) knockout mice have a bigger neointima after vascular injury and a larger infarct volume after stroke. The Marburg I (MI) single nucleotide polymorphism (SNP) in the FSAP-encoding gene is associated with an increased risk of stroke and carotid stenosis in humans. We hypothesize that the regulation of gene expression by FSAP in vascular cells accounts for its vasculo-regulatory properties.
Methods:
Vascular smooth muscle cells (VSMC) and endothelial cells (EC) were stimulated with FSAP and a microarray-based expression analysis was performed. Selected genes were further investigated by qPCR. Receptor- and pathway-inhibitors were used to elucidate the mechanisms involved.
Results:
Pathways significantly activated by FSAP include those related to inflammation, apoptosis and cell growth in VSMC and inflammation in EC. The key upregulated genes in VSMC were AREG, PTGS2 and IL6; and in EC these were SELE, VCAM1, and IL8. Secretion of IL6 in VSMC and IL8 in EC was also stimulated by FSAP. Recombinant wild type protease domain of FSAP, but not the MI-isoform, could recapitulate most of these effects. In VSMC, but not EC, gene expression by FSAP was impaired by PAR1 (protease-activated receptor1) receptor antagonists. In VSMC, FSAP-induced expression of AREG and IL6 was blocked by cAMP and MAPK pathway inhibitors indicating that multiple signalling pathways are likely to be involved.
Conclusions:
The stimulation of inflammation- and proliferative/apoptosis-related genes in VSMC and EC provides a comprehensive basis for understanding the role of FSAP in vascular diseases.
Insights
Factor VII activating protease (FSAP) influences vascular cell gene expression, impacting inflammation and cell growth. This provides insight into FSAP's role in vascular diseases like stroke.
Area of Science:
- Molecular biology and vascular cell signaling.
- Genetics and cardiovascular disease research.
Background:
- Factor VII activating protease (FSAP) knockout mice exhibit increased neointima formation and infarct volume.
- A specific FSAP gene polymorphism (Marburg I SNP) is linked to higher stroke and carotid stenosis risk in humans.
Purpose of the Study:
- To investigate the hypothesis that FSAP regulates gene expression in vascular cells, thereby influencing vascular health.
- To elucidate the molecular mechanisms underlying FSAP's vasculo-regulatory properties.
Main Methods:
- Stimulation of vascular smooth muscle cells (VSMC) and endothelial cells (EC) with FSAP.
- Microarray analysis to assess gene expression changes.
- Quantitative PCR (qPCR) for validating gene expression.
- Use of receptor and pathway inhibitors to identify signaling mechanisms.
Main Results:
- FSAP significantly activated inflammation, apoptosis, and cell growth pathways in VSMC, and inflammation in EC.
- Key upregulated genes included AREG, PTGS2, and IL6 in VSMC, and SELE, VCAM1, and IL8 in EC.
- FSAP stimulated IL6 and IL8 secretion; wild-type FSAP, but not the MI-isoform, replicated these effects.
- FSAP-induced gene expression in VSMC was partly mediated by PAR1 and involved cAMP and MAPK signaling pathways.
Conclusions:
- FSAP stimulation of inflammation- and proliferation/apoptosis-related genes in VSMC and EC offers a molecular basis for its role in vascular diseases.
- Understanding these pathways is crucial for developing targeted therapies for FSAP-associated vascular conditions.
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