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Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

Kardeby, Caroline, 1989- (författare)
Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
Fälker, Knut, 1971- (författare)
Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
Haining, Elizabeth J. (författare)
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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Criel, Maarten (författare)
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
Lindkvist, Madelene, 1984- (författare)
Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
Barroso, Ruben (författare)
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom
Påhlsson, Peter, 1962- (författare)
Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom
Ljungberg, Liza, 1980- (författare)
Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
Tengdelius, Mattias, 1984- (författare)
Linköpings universitet,Kemi,Tekniska fakulteten
Rainger, G. Ed. (författare)
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
Watson, Stephanie (författare)
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
Eble, Johannes A. (författare)
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany; and
Hoylaerts, Marc F. (författare)
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
Emsley, Jonas (författare)
Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom; Division of Biomolecular Science and Medicinal Chemistry, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
Konradsson, Peter (författare)
Linköpings universitet,Kemi,Tekniska fakulteten
Watson, Steve P. (författare)
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom
Sun, Yi (författare)
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom
Grenegård, Magnus, 1963- (författare)
Örebro universitet,Institutionen för medicinska vetenskaper,Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
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 (creator_code:org_t)
2019-01-30
2019
Engelska.
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:3, s. 275-287
Relaterad länk:
https://ashpublicati...
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https://urn.kb.se/re...
https://doi.org/10.1...
https://urn.kb.se/re...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

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