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A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).ORCID-id: 0000-0002-5025-9454
Örebro universitet, Institutionen för medicinska vetenskaper. 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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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
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URN: urn:nbn:se:oru:diva-74034OAI: oai:DiVA.org:oru-74034DiVA, id: diva2:1313742
Tilgjengelig fra: 2019-05-06 Laget: 2019-05-06 Sist oppdatert: 2019-05-06bibliografisk kontrollert
Inngår i avhandling
1. Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
Åpne denne publikasjonen i ny fane eller vindu >>Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Örebro: Örebro University, 2019. s. 64
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 195
Emneord
Haemostasis, glycopolymers, purine analogue, PEAR1, GPIbα, CLEC-2, inflammation, ROCK
HSV kategori
Identifikatorer
urn:nbn:se:oru:diva-73147 (URN)978-91-7529-287-8 (ISBN)
Disputas
2019-05-29, Örebro universitet, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 13:00 (engelsk)
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Veileder
Tilgjengelig fra: 2019-03-14 Laget: 2019-03-14 Sist oppdatert: 2019-05-06bibliografisk kontrollert

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Kardeby, CarolineParamel Varghese, GeenaSirsjö, AllanFransén, KarinGrenegård, Magnus

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