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Release of ADP or PAR4 Activation is Required to Sustain Thrombin-induced Platelet Aggregation
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-1920-3962
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Thrombin activates human platelets through cleavage of two G-protein-coupled proteaseactivatedreceptors (PARs) denoted PAR1 and PAR4. The aim of this study was to investigatedifferences in PAR1 and PAR4 signaling regarding formation and stability of plateletaggregates. We show that weak PAR1-mediated aggregation is reversible, whereas PAR4-mediated aggregation, weak or strong, is always sustained. PAR1-induced plateletaggregation is decreased and more reversible in the presence of the P2Y12 antagonistcangrelor. However, the effects by cangrelor can be concentration-dependently reversed byconcomitant PAR4 activation in a PI3-kinase-dependent manner. In contrast; in PAR4-APstimulated platelets, aggregation is reduced by cangrelor or inhibition of PI3-kinase byLY294002 but remains irreversible. However, a combined inhibition of PI3-K and P2Y12results in reduced and reversible aggregation. In the light of recently published data on PAR1desensitization, we suggest that the physiological role of the differences between PAR1 andPAR4 activation on aggregate and clot stability could be to fine-tune the response tothrombin. A repeated or continuous very low thrombin generation will desensitize PAR1 andeven if small platelet aggregates are formed they will dissolve, preventing inappropriatethrombus formation. At higher concentrations of thrombin, PAR4 will become activatedabrogating desensitization of PAR1 and enforcing stability of platelet aggregates.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71394OAI: oai:DiVA.org:liu-71394DiVA: diva2:448088
Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2015-03-13Bibliographically approved
In thesis
1. The role of platelet thrombin receptors PAR1 and PAR4 in health and disease
Open this publication in new window or tab >>The role of platelet thrombin receptors PAR1 and PAR4 in health and disease
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Blood cells are continuously flowing in our systems maintaining haemostasis in the arteries and veins. If a vessel is damaged, the smallest cell fragments in the blood (platelets) are directed to cover the wound and plug the leakage to prevent blood loss. Most of the time platelets stop the blood leak without any difficulties. During other, pathological, circumstances, platelets continue to form a thrombus, preventing the blood flow and may cause myocardial infarction or stroke.

Thrombin is the most potent platelet agonist and is a product created in the coagulation cascade. This thesis is focused on the interactions between the two platelet thrombin receptors; protease activated receptors 1 (PAR1) and PAR4 in vitro. We have investigated potential differences between these receptors in several situations associated with cardiovascular disease.

First we studied interactions between PAR1 and PAR4 and the oral pathogen Porphyromonas gingivalis (which secretes enzymes, gingipains, with properties similar to thrombin). Here we showed that P. gingivalis is signaling mainly, but not exclusively, via PAR4. Our second study showed that the cross-talk between the stress hormone epinephrine and thrombin occur exclusively through PAR4 if the key-substance ATP is present and cyclooxygenase-1 inhibited by aspirin. The third study investigated platelet secretion, with focus on the protein plasminogen activator inhibitor 1(PAI-1), an inhibitor of the fibrinolytic process responsible for dissolving a formed clot. Here we showed that PAI-1 secretion and synthesis was more sensitive to stimulation through PAR1 than PAR4. Finally this thesis describes differences between PAR1 and PAR4 in cell-signaling pathways regulating the stability of a platelet aggregate, where PAR4 seems to be of importance to create stable platelet aggregates and that this stability is dependent on ADP activation via P2Y12 and cell signaling via PI3-kinase.

Until now, PAR1 has been considered to be the most important thrombin receptor, due to its high affinity for thrombin. However, there must be a reason why platelets express two different thrombin receptors. This thesis highlights several situations where PAR4 plays a complementary and important role in platelet signaling and haemostasis.

In conclusion, this thesis suggests that PAR4 plays a major role in calcium signaling and the induction of sustained aggregation, while PAR1 shows a more prominent role in platelet secretion and synthesis. This thesis also reveals new interactions between platelet thrombin receptors and the ADP-, ATP- and epinephrine receptors. The results described in this thesis contribute to an increased knowledge of the platelet thrombin receptors and their interplay in situations such as infection, stress, fibrinolysis, and platelet aggregation.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 63 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1261
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71395 (URN)978-91-7393-067-3 (ISBN)
Public defence
2011-11-04, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2011-11-28Bibliographically approved

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Nylander, MartinaFälker, KnutRamström, SofiaGrenegård, MagnusLindahl, Tomas

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