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Vascular patho-physiology

The goal of our research is to reduce the level of cardiovascular disease by developing new diagnostic methods and treatment strategies.

X-ray of a skull suffering from a stroke, affected area colorized in red

Illustration: Colourbox

About the group

We perform basic research in vascular biology with the aim to understand and solve outstanding problems in cardiovascular medicine. In particular, circulating factors which are components of the coagulation and fibrinolysis system are being investigated.

This research is relevant for diseases such as atherosclerosis, myocardial infarction, stroke and thrombosis. The mechanisms involved are also relevant for allied processes such as tissue repair, fibrosis, host defense, inflammation and cancer.

Collaborations

  • Jonas Emsley, Nottingham, UK (Protein structure function, X-ray crystallography)
  • Christina Jern, Gothenburg, Sweden (Stroke diagnosis and GWAS)
  • Paul Declerck, Leuven, Belgium (Serine protease inhibitors and monoclonal antibodies)
  • Eric Camerer, Paris, France (Protease-activated receptors)
  • Denis Vivien, Caen, France (Mouse models of stroke)
  • Michael Etscheid, Langen, Germany (FSAP biochemistry and thrombosis)
  • Christoph Reichel, Munich, Germany (Proteases and leukocyte transmigration)
  • Trygve Braun Leergaard, Oslo, Norway (Rodent neuroanatomical mapping)
  • Per Morten Sandset, Oslo, Norway (Thrombosis)
  • Geir Åge Løset, Oslo, Norway (Phage display)
  • Hartmut Luecke, Oslo, Norway (Protein structure function, cryo-electron microscopy)
  • Kristi Bache, Oslo, Norway (Stroke-Diagnosis)

Challenges

Cardiovascular diseases are a major cause of mortality and morbidity worldwide. The overall goal of this research is to reduce the level of cardiovascular disease by developing new diagnostic methods and treatment strategies. Being at the interface between many inter-related processes the coagulation and fibrinolysis system will provide many possibilities for their eventual manipulation. By gaining a better mechanistic understanding of these circulating factors, we want to realize our goals.

Recent achievements

A SNP in the gene encoding for FSAP is a risk factor for atherosclerosis and stroke. We have performed numerous studies to understand the functions of FSAP with respect to neointima formation (Kannemeier et al, FASEB J, 2004; Sedding et al, J Exp Med, 2006; Daniel et al, J Thromb & Haem 2016) arteriogenesis (Herold et al, Am J Trans Med, 2017) and angiogenesis (Uslu et al, Cells, 2019). FSAP-/- mice exhibit a poor outcome after induction of stroke (Joshi et al, Eur J Neurosc 2015) and are protected against thrombosis (Subramaniam et al, Thromb & Haem 2015).

Furthermore, we have identified a novel substrate for FSAP in the circulation, tissue factor pathway inhibitor, complement proteins and fibrinogen, which will help to elucidate its function (Kanse et al, Arterioscler Thromb Vasc Biol, 2012 and J Immunol, 2012; Etscheid et al, Biochim Biophys Acta, 2018).

We have expanded on the concept of tissue injury-mediated release of histones activating pro-FSAP to the activation of pro-FSAP by artificial surfaces (Sperling et al, ACS Appl Mat & Int, 2017), by neutrophil extracellular traps (NETs) (Grasso et al, 2018) and peptides identified by phage display (manuscript in preparation).

Using phage display and synthetic peptide substrate libraries we have characterized the substrate specificity of FSAP and have developed new selective substrates (Kara et al, Thromb & Haem 2017). We have now extended these studies to synthetic peptide substrate libraries made of non-standard amino acids (Rut et al, Thromb Res 2019).

We have established methods to produce recombinant FSAP domains in bacteria for detailed structure-function studies (Nielsen et al, Scientific Reports, 2019).

We have established the role of protease-activated receptors in mediating the cellular effects of FSAP (Byskov et al, Atherosclerosis, 2016 and Byskov et al, FASEB J, 2020)

We have discovered a new function for FSAP in liver fibrosis by investigating its expression in liver fibrosis, and by determining the correlations of SNPs in the gene encoding for FSAP with the severity of liver fibrosis. FSAP-/- mice exhibit enhanced liver fibrosis. (Roderfeld et al, Liv Int 2009; Wasmuth et al, Hepatology, 2009, Borkham-Kamphorst et al, 2013).

We have characterized the pathways and transcription factors regulating the expression of FSAP in hepatocytes (Leiting et al, J Biol Chem, 2015) and have identified novel genes involved in this regulation through GWAS studies (Olsson et al, J Thromb & Haem 2017)

Projects 

  • The influence of FSAP on the outcome of stroke in mouse models? Lab member: Jeong-Yeon Kim.  External cooperation partners: Denis Vivien, Caen, France and Trygve Braun Leergaard, Oslo, Norway.
  • Structure-function studies and protein biochemistry of FSAP. Lab member: Nis Valentin Nielsen, Dipankar Manna. External cooperation partners: Hartmut Lueke, Oslo, Norway and Jonas Emsley, Nottingham, UK
  • Characterization of the interaction partners and receptors of FSAP in the circulation and on cells? Lab member: Kristina Byskov. External cooperation partners: Michael Etscheid, Langen, Germany and Eric Camerer, Paris, France.
  • Use phage display library to identify peptides that modulate FSAP activity. Lab members: Sebastian Seidl and Nis Valentin Nielsen. External cooperation partners: Geir Åge Løset, Oslo, Norway and Bengt-Erik Haug, Bergen, Norway.

Publications


1.    Byskov K, Le Gall SM, Thiede B, Camerer E and Kanse SM. Protease activated receptors (PAR)-1 and -2 mediate cellular effects of factor VII activating protease (FSAP). The FASEB Journal. 2020; In press.
2.    Uslu O, Herold J and Kanse SM. VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization. Cells. 2019; 8.
3.    Rut W, Nielsen NV, Czarna J, Poreba M, Kanse SM and Drag M. Fluorescent activity-based probe for the selective detection of Factor VII activating protease (FSAP) in human plasma. Thrombosis research. 2019;182:124-132.
4.    Nielsen NV, Roedel E, Manna D, Etscheid M, Morth JP and Kanse SM. Characterization of the enzymatic activity of the serine protease domain of Factor VII activating protease (FSAP). Scientific Reports. 2019; In Press.
5.    Dahm AEA, Jacobsen EM, Wik HS, Jacobsen AF, Mollnes TE, Kanse SM and Sandset PM. Elevated Complement C3 and C4 Levels are Associated with Postnatal Pregnancy-Related Venous Thrombosis. Thromb Haemost. 2019;119:1481-1488.
6.    Bohnert BN, Kanse S, Haerteis S, Korbmacher C and Artunc F. Rebuttal to Editorial: sodium retention by uPA in nephrotic syndrome? Acta physiologica (Oxford, England). 2019:e13427.
7.    Bohnert BN, Daiminger S, Worn M, Sure F, Staudner T, Ilyaskin AV, Batbouta F, Janessa A, Schneider JC, Essigke D, Kanse S, Haerteis S, Korbmacher C and Artunc F. Urokinase-type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)-mediated sodium retention in experimental nephrotic syndrome. Acta physiologica (Oxford, England). 2019:e13286.
8.    Subramaniam S, Kanse SM, Kothari H, Reinhardt C and Fletcher C. Post-transcriptional, post-translational and pharmacological regulation of tissue factor pathway inhibitor. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2018;29:668-682.
9.    Praetner M, Zuchtriegel G, Holzer M, Uhl B, Schaubacher J, Mittmann L, Fabritius M, Furst R, Zahler S, Funken D, Lerchenberger M, Khandoga A, Kanse S, Lauber K, Krombach F and Reichel CA. Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia-Reperfusion. Arteriosclerosis, thrombosis, and vascular biology. 2018;38:829-842.
10.    Olsson M, Stanne TM, Pedersen A, Lorentzen E, Kara E, Martinez-Palacian A, Ronnow Sand NP, Jacobsen AF, Sandset PM, Sidelmann JJ, Engstrom G, Melander O, Kanse SM and Jern C. Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity. Journal of thrombosis and haemostasis :  2018;16:2024-2034.
11.    Grasso S, Neumann A, Lang IM, Etscheid M, von Kockritz-Blickwede M and Kanse SM. Interaction of factor VII activating protease (FSAP) with neutrophil extracellular traps (NETs). Thrombosis research. 2018;161:36-42.
12.    Etscheid M, Subramaniam S, Lochnit G, Zabczyk M, Undas A, Lang IM, Hanschmann KM and Kanse SM. Altered structure and function of fibrinogen after cleavage by Factor VII Activating Protease (FSAP). Biochim Biophys Acta Mol Basis Dis. 2018;1864:3397-3406.
13.    Cole JW, Xu H, Ryan K, Jaworek T, Dueker N, McArdle P, Gaynor B, Cheng YC, O'Connell J, Bevan S, Malik R, Ahmed NU, Amouyel P, Anjum S, Bis JC, Crosslin D, Danesh J, Engelter ST, Fornage M, Frossard P, Gieger C, Giese AK, Grond-Ginsbach C, Ho WK, Holliday E, Hopewell J, Hussain M, Iqbal W, Jabeen S, Jannes J, Kamal A, Kamatani Y, Kanse S, Kloss M, Lathrop M, Leys D, Lindgren A, Longstreth WT, Jr., Mahmood K, Meisinger C, Metso TM, Mosley T, Jr., Muller-Nurasyid M, Norrving B, Parati E, Peters A, Pezzini A, Quereshi I, Rasheed A, Rauf A, Salam T, Shen J, Slowik A, Stanne T, Strauch K, Tatlisumak T, Thijs VN, Tiedt S, Traylor M, Waldenberger M, Walters M, Zhao W, Boncoraglio G, Debette S, Jern C, Levi C, Markus H, Meschia J, Rolfs A, Rothwell P, Saleheen D, Seshadri S, Sharma P, Sudlow C, Worrall B, Stine OC, Kittner SJ and Mitchell BD. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. PloS one. 2018;13:e0206554.
14.    Sperling C, Maitz MF, Grasso S, Werner C and Kanse SM. A Positively Charged Surface Triggers Coagulation Activation Through Factor VII Activating Protease (FSAP). ACS applied materials & interfaces. 2017;9:40107-40116.
15.    Reiterer V, Figueras-Puig C, Le Guerroue F, Confalonieri S, Vecchi M, Jalapothu D, Kanse SM, Deshaies RJ, Di Fiore PP, Behrends C and Farhan H. The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function. EMBO J. 2017;36:260-273.
16.    Kara E, Manna D, Loset GA, Schneider EL, Craik CS and Kanse S. Analysis of the substrate specificity of Factor VII activating protease (FSAP) and design of specific and sensitive peptide substrates. Thromb Haemost. 2017;117:1750-1760.
17.    Herold J, Nowak S, Kostin S, Daniel JM, Francke A, Subramaniam S, Braun-Dullaeus RC and Kanse SM. Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model. Am J Transl Res. 2017;9:3084-3095.
18.    Byskov K, Boettger T, Ruehle PF, Nielsen NV, Etscheid M and Kanse SM. Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells. Atherosclerosis. 2017;265:133-139.
19.    Leiting S, Seidl S, Martinez-Palacian A, Muhl L and Kanse SM. Transforming Growth Factor-beta (TGF-beta) Inhibits the Expression of Factor VII-activating Protease (FSAP) in Hepatocytes. The Journal of biological chemistry. 2016;291:21020-21028.
20.    Daniel JM, Reichel CA, Schmidt-Woell T, Dutzmann J, Zuchtriegel G, Krombach F, Herold J, Bauersachs J, Sedding DG and Kanse SM. Factor VII-activating protease deficiency promotes neointima formation by enhancing leukocyte accumulation. Journal of thrombosis and haemostasis : 2016;14:2058-2067.
21.    Cui XY, Tinholt M, Stavik B, Dahm AE, Kanse S, Jin Y, Seidl S, Sahlberg KK, Iversen N, Skretting G and Sandset PM. Effect of hypoxia on tissue factor pathway inhibitor expression in breast cancer. Journal of thrombosis and haemostasis : 2016;14:387-96.
22.    Chillo O, Kleinert EC, Lautz T, Lasch M, Pagel JI, Heun Y, Troidl K, Fischer S, Caballero-Martinez A, Mauer A, Kurz ARM, Assmann G, Rehberg M, Kanse SM, Nieswandt B, Walzog B, Reichel CA, Mannell H, Preissner KT and Deindl E. Perivascular Mast Cells Govern Shear Stress-Induced Arteriogenesis by Orchestrating Leukocyte Function. Cell Rep. 2016;16:2197-2207.
23.    Cheng YC, Stanne TM, Giese AK, Ho WK, Traylor M, Amouyel P, Holliday EG, Malik R, Xu H, Kittner SJ, Cole JW, O'Connell JR, Danesh J, Rasheed A, Zhao W, Engelter S, Grond-Ginsbach C, Kamatani Y, Lathrop M, Leys D, Thijs V, Metso TM, Tatlisumak T, Pezzini A, Parati EA, Norrving B, Bevan S, Rothwell PM, Sudlow C, Slowik A, Lindgren A, Walters MR, Consortium W-, Jannes J, Shen J, Crosslin D, Doheny K, Laurie CC, Kanse SM, Bis JC, Fornage M, Mosley TH, Hopewell JC, Strauch K, Muller-Nurasyid M, Gieger C, Waldenberger M, Peters A, Meisinger C, Ikram MA, Longstreth WT, Jr., Meschia JF, Seshadri S, Sharma P, Worrall B, Jern C, Levi C, Dichgans M, Boncoraglio GB, Markus HS, Debette S, Rolfs A, Saleheen D and Mitchell BD. Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. Stroke. 2016;47:307-16.
24.    Bustamante A, Diaz-Fernandez B, Giralt D, Boned S, Pagola J, Molina CA, Garcia-Berrocoso T, Kanse SM and Montaner J. Factor seven activating protease (FSAP) predicts response to intravenous thrombolysis in acute ischemic stroke. International journal of stroke: 2016;11:646-55.
25.    Subramaniam S, Thielmann I, Morowski M, Pragst I, Sandset PM, Nieswandt B, Etscheid M and Kanse SM. Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP). Thromb Haemost. 2015;113:870-80.
26.    Reichel CA, Hessenauer ME, Pflieger K, Rehberg M, Kanse SM, Zahler S, Krombach F, Berghaus A and Strieth S. Components of the plasminogen activation system promote engraftment of porous polyethylene biomaterial via common and distinct effects. PloS one. 2015;10:e0116883.
27.    Joshi AU, Orset C, Engelhardt B, Baumgart-Vogt E, Gerriets T, Vivien D and Kanse SM. Deficiency of Factor VII activating protease alters the outcome of ischemic stroke in mice. Eur J Neurosci. 2015;41:965-75.

 

 

Tags: Cardiovascular diseases, stroke, thrombosis, atherosclerosis, coagulation, fibrinolysis. proteases, Blood and immunology
Published Jan. 13, 2012 1:40 PM - Last modified Feb. 26, 2020 12:14 PM

Contact

Mailing address
P.O.Box 1112 Blindern
0317 Oslo

Visiting address
Domus Medica, Gaustad
Sognsvannsveien 9
0372 Oslo

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