Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear
| Autor: | Gina Perrella, Samantha J. Montague, Helena C. Brown, Lourdes Garcia Quintanilla, Alexandre Slater, David Stegner, Mark Thomas, Johan W. M. Heemskerk, Steve P. Watson |
|---|---|
| Přispěvatelé: | Biochemie, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Platelet Aggregation
QH301-705.5 SYSTEMS-APPROACH Platelet Glycoprotein GPIIb-IIIa Complex Platelet Membrane Glycoproteins Catalysis Article Inorganic Chemistry ACTIVATION Platelet Adhesiveness GPVI Humans Syk Kinase Syk ddc:610 cardiovascular diseases Physical and Theoretical Chemistry Biology (General) Phosphorylation disaggregation platelet thrombus tyrosine kinase Molecular Biology QD1-999 Spectroscopy Organic Chemistry Temperature Thrombin Thrombosis General Medicine Single-Domain Antibodies ANTIPLATELET PLATELETS Computer Science Applications Chemistry Collagen Shear Strength circulatory and respiratory physiology |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 1; Pages: 493 International Journal of Molecular Sciences, 23(1):493. Multidisciplinary Digital Publishing Institute (MDPI) International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 23, Iss 493, p 493 (2022) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23010493 |
| Popis: | Understanding the pathways involved in the formation and stability of the core and shell regions of a platelet-rich arterial thrombus may result in new ways to treat arterial thrombosis. The distinguishing feature between these two regions is the absence of fibrin in the shell which indicates that in vitro flow-based assays over thrombogenic surfaces, in the absence of coagulation, can be used to resemble this region. In this study, we have investigated the contribution of Syk tyrosine kinase in the stability of platelet aggregates (or thrombi) formed on collagen or atherosclerotic plaque homogenate at arterial shear (1000 s−1). We show that post-perfusion of the Syk inhibitor PRT-060318 over preformed thrombi on both surfaces enhances thrombus breakdown and platelet detachment. The resulting loss of thrombus stability led to a reduction in thrombus contractile score which could be detected as early as 3 min after perfusion of the Syk inhibitor. A similar loss of thrombus stability was observed with ticagrelor and indomethacin, inhibitors of platelet adenosine diphosphate (ADP) receptor and thromboxane A2 (TxA2), respectively, and in the presence of the Src inhibitor, dasatinib. In contrast, the Btk inhibitor, ibrutinib, causes only a minor decrease in thrombus contractile score. Weak thrombus breakdown is also seen with the blocking GPVI nanobody, Nb21, which indicates, at best, a minor contribution of collagen to the stability of the platelet aggregate. These results show that Syk regulates thrombus stability in the absence of fibrin in human platelets under flow and provide evidence that this involves pathways additional to activation of GPVI by collagen. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |