The aim of this project is to identify the mechanism of action of factor VII activating protease (FSAP) in vascular diseases and to further develop its diagnostic and therapeutic potential
Final Report Abstract
The possibility to analyze single nucleotide polymorphisms (SNPs), across the population has thrown up a plethora of genes that are predictors of atherosclerosis and related events. The SNP rs7080536, also called Marburg I (MI) SNP in the hyaluronic acid binding protein-2 (HABP2) gene is a risk factor for carotid stenosis, thrombosis and stroke. This gene encodes for a circulating protease called factor seven activating protease (FSAP) and 5% of Europeans are carriers of this SNP. We have found that the MI-isoform of FSAP has lower proteolytic activity towards all substrates tested. This polymorphism, or mutation, provides an opportunity to explore the role of this gene in human disease and to identify novel molecular mechanisms. FSAP is secreted by the liver and found in the circulation as an inactive pro-form without any enzymatic activity. Nuclear components released by damaged cells, such as nucleosomes and histones, are potent activators of the FSAP zymogen. We have successfully demonstrated this principle in humans by showing that in patients with multiple trauma there was a large increase in FSAP activity which correlated strongly with an increase in circulating nucleosomes. In relation to the cardiovascular system we have performed some investigations using FSAP-/- mice and have collected convincing results indicating the importance of FSAP for these processes. In the vascular injury model, FSAP-/- mice exhibited higher neointima formation and stroke-related brain damage but were protected against thrombosis. These results are compatible with our findings that FSAP-/- mice exhibited enhanced fibrosis which was accompanied by a stronger inflammatory response in the liver. Chronic inflammatory diseases, such as atherosclerosis, usually arise due to a lack of resolution of inflammation and thus activation of the FSAP-pathway could be of therapeutic value in various cardiovascular diseases.
Publications
- Factor VII Activating Protease Polymorphism (G534E) Is Associated with Increased Risk for Stroke and Mortality. Stroke research and treatment. 2011;2011:424759
Trompet S, Pons D, Kanse SM, de Craen AJ, Ikram MA, Verschuren JJ, Zwinderman AH, Doevendans PA, Tio RA, de Winter RJ, Slagboom PE, Westendorp RG and Jukema JW
- Factor VII-activating protease is activated in multiple trauma patients and generates anaphylatoxin C5a. Journal of Immunol. 2012;188:2858-65
Kanse SM, Gallenmueller A, Zeerleder S, Stephan F, Rannou O, Denk S, Etscheid M, Lochnit G, Krueger M and Huber-Lang M
(See online at https://doi.org/10.4049/jimmunol.1103029) - Factor VII-activating protease promotes the proteolysis and inhibition of tissue factor pathway inhibitor. Arteriosclerosis, thrombosis, and vascular biology. 2012;32:427-33
Kanse SM, Declerck PJ, Ruf W, Broze G and Etscheid M
(See online at https://doi.org/10.1161/ATVBAHA.111.238394) - Plasma factor VII-activating protease antigen levels and activity are increased in ischemic stroke. Journal of thrombosis and haemostasis. 2012;10:848-56
Hanson E, Kanse SM, Joshi A, Jood K, Nilsson S, Blomstrand C and Jern C
(See online at https://doi.org/10.1111/j.1538-7836.2012.04692.x) - Factor VII activating protease (FSAP) exerts antiinflammatory and anti-fibrotic effects in liver fibrosis in mice and men. Journal of hepatology. 2013;58:104-11
Borkham-Kamphorst E, Zimmermann HW, Gassler N, Bissels U, Bosio A, Tacke F, Weiskirchen R and Kanse SM
(See online at https://doi.org/10.1016/j.jhep.2012.09.007) - Regulation of monocyte/macrophage function by factor VII activating protease (FSAP). Atherosclerosis. 2013;230:365-72
Parahuleva MS, Maj R, Holschermann H, Parviz B, Abdallah Y, Erdogan A, Tillmanns H and Kanse SM
- The Factor VII-activating protease (FSAP) enhances the activity of bone morphogenetic protein-2 (BMP-2). The Journal of biological chemistry. 2013;288:11
Roedel EK, Schwarz E and Kanse SM
(See online at https://doi.org/10.1074/jbc.M112.433029) - Defective thrombus formation in mice lacking endogenous Factor VII activating protease (FSAP). Thrombosis and haemostasis Thromb Haemost 2015; 113(04): 870-880
Subramaniam S, Thielmann I, Morowski M, Pragst I, Sanset PM, Nieswandt B, Etscheid M and Kanse SM
(See online at https://doi.org/10.1160/TH14-06-0519)
