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Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping , Sweden.
Örebro University, School of Medical Sciences. (Cardiovascular Research Centre)ORCID iD: 0000-0002-5025-9454
Örebro University, School of Medical Sciences. (Cardiovascular Research Centre)ORCID iD: 0000-0003-2519-203X
Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
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2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed) Published
Abstract [en]

The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α-l-fucoside-pendant poly(methacryl amides) with homogeneous structures. By using both thiol-mediated chain transfer and reversible addition-fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan-mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.

Place, publisher, year, edition, pages
Weinheim, Germany: Wiley-VCH Verlagsgesellschaft, 2017. Vol. 17, no 2, article id UNSP 1600257
Keywords [en]
biological applications of polymers; biomimetic; radical polymerization; reversible addition fragmentation chain transfer; structure-property relations
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:oru:diva-52179DOI: 10.1002/mabi.201600257ISI: 000394592600012PubMedID: 27616165Scopus ID: 2-s2.0-84987653303OAI: oai:DiVA.org:oru-52179DiVA, id: diva2:972620
Note

Funding Agency:

AFA Insurance, VR Treatments of the Future grant

Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2019-05-06Bibliographically approved
In thesis
1. Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
Open this publication in new window or tab >>Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Haemostasis is a complex and tightly regulated process which protects us from bleeding. Platelets are essential for maintained haemostasis. Under normal conditions platelets are calmed by antithrombotic substances release by the endothelium. During vascular injury, the platelets will activate and form a haemostatic plug to prevent bleeding. Inflammatory processes like atherosclerosis can disturb the haemostatic balance and lead to severe consequences like myocardial infarction and stroke. Inhibition of platelets and coagulation are common treatments to prevent unwanted blood clot formation. There is a great need for increased knowledge on the mechanisms of thrombosis and characterisation of new substances with possible therapeutic potential. This thesis used unique synthetic drugs to study platelet signalling and endothelial responses. Paper I showed that both sulfated polysaccharides from seaweed and synthetic glycopolymers which mimic their chemical properties caused platelet activation.

Paper II elucidated the molecular mechanism underlying platelet activation by sulfated glycopolymers and polysaccharides. We found that human platelet activation took place via the Platelet endothelial aggregation receptor 1 (PEAR1), while mouse platelet activation was mainly via C-type lectin-like receptor 2. Aggregation was supported by Glycoprotein Ibα in both species.

Paper III showed the effect of synthetic glycopolymers and natural polysaccharides on cultured human endothelial cells. We found that both the glycopolymers and polysaccharides caused a proinflammatory response after 24h.

In Paper IV, the effect of a synthetic purine analogue with a nitrate ester motif was studied. We found that the purine analogue reduced platelet functions by inhibiting Rho-associated protein kinase (ROCK).

This thesis describes unique synthetic drugs that can be used for further studies of the mechanisms underlying the biological processes of thrombosis and inflammation. The synthetic glycopolymers can be used to further elucidate the physiological role of PEAR1, a potential future therapeutic target.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2019. p. 64
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 195
Keywords
Haemostasis, glycopolymers, purine analogue, PEAR1, GPIbα, CLEC-2, inflammation, ROCK
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-73147 (URN)978-91-7529-287-8 (ISBN)
Public defence
2019-05-29, Örebro universitet, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 13:00 (English)
Opponent
Supervisors
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-05-06Bibliographically approved

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