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A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).ORCID iD: 0000-0002-5025-9454
Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).ORCID iD: 0000-0002-4589-6440
National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
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(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:oru:diva-74034OAI: oai:DiVA.org:oru-74034DiVA, id: diva2:1313742
Available from: 2019-05-06 Created: 2019-05-06 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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Kardeby, CarolineParamel Varghese, GeenaSirsjö, AllanFransén, KarinGrenegård, Magnus

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