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Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
Örebro University, School of Medical Sciences.ORCID iD: 0000-0002-5025-9454
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 [en]
Haemostasis, glycopolymers, purine analogue, PEAR1, GPIbα, CLEC-2, inflammation, ROCK
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:oru:diva-73147ISBN: 978-91-7529-287-8 (print)OAI: oai:DiVA.org:oru-73147DiVA, id: diva2:1296231
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
List of papers
1. Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
Open this publication in new window or tab >>Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
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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
Keywords
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:nbn:se:oru:diva-52179 (URN)10.1002/mabi.201600257 (DOI)000394592600012 ()27616165 (PubMedID)2-s2.0-84987653303 (Scopus ID)
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
2. Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
Open this publication in new window or tab >>Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
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2019 (English)In: Blood advances, ISSN 2473-9529, Vol. 3, no 3, p. 275-287Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society of Hematology, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agencies:

BHF  PG/16/53/32242  RG/13/18/30563 

Deutsche Forschungsgemeinschaft  DFG: Eb 177/14-1 

Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant  G0A6514N 

Available from: 2019-02-14 Created: 2019-02-14 Last updated: 2019-06-18Bibliographically approved
3. Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
Open this publication in new window or tab >>Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-74033 (URN)
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
4. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
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(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-74034 (URN)
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved

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