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The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
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 Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 129, no 4, E51-E58 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION:

Arterial thrombi contain more platelets than venous thrombi and are more resistant to fibrinolysis. This resistance could partly be due to plasminogen activator inhibitor 1 (PAI-1) secreted by platelets. The aim of this study was to elucidate differences between thrombin receptors protease-activated receptor (PAR) 1 and 4 and platelet storage, secretion and synthesis of platelet PAI-1, as compared to other platelet α-granule proteins such as VEGF and endostatin.

MATERIALS AND METHODS:

Human isolated platelets were incubated with thrombin (0.5U/ml), PAR1-activating peptide (AP) (0.4-30μM) or PAR4-AP (1.5-300μM) for up to 24hours. ELISA, western blot and fluorescence microscopy were used to measure secretion, contents and localization of PAI-1, VEGF and endostatin.

RESULTS:

Our results show that PAI-1 and VEGF might be co-localized and that endostatin does not co-localize with either PAI-1 or VEGF. PAI-1 and VEGF show a similar secretion pattern, being more sensitive to low grade PAR1 activation, but secretion was also observed with higher concentrations of PAR4-APs. PAI-1 is secreted in an active form. PAI-1 mRNA was found in platelets, and elevated levels of PAI-1 were detected after 24hours incubation of platelets.

CONCLUSIONS:

PAI-1 and VEGF, but not endostatin, might be stored in the same α-granule in human platelets. PAI-1 and VEGF also show a similar secretion pattern, being more sensitive to PAR1 than to PAR4 activation, but the secretion is not exclusively selective. Our results also show that platelet PAI-1 is increased if incubated for 24hours, both with addition of PAR1-activating peptide and without activation, which could indicate de novo synthesis.

Place, publisher, year, edition, pages
Elsevier, 2012. Vol. 129, no 4, E51-E58 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71393DOI: 10.1016/j.thromres.2011.12.021ISI: 000301587400010OAI: oai:DiVA.org:liu-71393DiVA: diva2:448087
Note

funding agencies|Swedish Research Council| K2010-65X-15060-07-3 |strategic research area Cardiovascular Inflammation Research Center (CIRC)||County Council of Ostergotland||University of Linkoping||

Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2017-12-08Bibliographically 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)
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Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2011-11-28Bibliographically approved

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Nylander, MartinaOsman, AbdimajidRamström, SofiaLindahl, Tomas

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