Leu33Pro (PlA) polymorphism of integrin beta3 modulates platelet Src pY418 and focal adhesion kinase pY397 phosphorylation in response to abnormally high shear stress
| Autor: | Phuong T. K. Nguyen, Marianna Gyenes, Thi-Hiep Nguyen, Khon Huynh, Ngoc Quyen Tran, Van Toi Vo, Volker R. Stoldt |
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| Rok vydání: | 2018 |
| Předmět: |
Blood Platelets
0301 basic medicine Integrin Polymorphism Single Nucleotide Focal adhesion 03 medical and health sciences Platelet Adhesiveness Platelet adhesiveness Abciximab medicine Humans Platelet Phosphorylation biology Chemistry Kinase Integrin beta3 Hematology General Medicine Cell biology Enzyme Activation src-Family Kinases 030104 developmental biology Focal Adhesion Kinase 1 biology.protein Stress Mechanical Blood Flow Velocity medicine.drug Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Blood Coagulation & Fibrinolysis. 29:488-495 |
| ISSN: | 0957-5235 |
| Popis: | Objectives Shear stress can activate platelet integrin-mediated signaling that leads to shear-induced platelet aggregation (SIPA) and eventually contribute to acute myocardial infarction. The major platelet integrin αIIbβ3 is polymorphic at residue 33 [Leu33Pro (PlA) polymorphism]. The Pro33 isoform has been shown to have a prothrombotic phenotype. In this work, we studied the impact of Leu33/Pro33 polymorphism on the shear-induced integrin-mediated Src and FAK activation in platelets. Methods Platelets of both genotypes were placed on immobilized fibrinogen or heat activated BSA and were exposed to physiological (500/s) or abnormally high (5000/s) shear rates for 2-10 min. Platelets after exposure to shear were analysed for Src pY418 and FAK pY397 activities. Results Whereas physiological shear stress does not affect platelet signaling, abnormally high-shear stress considerably elevates Src and FAK phosphorylation in both Pro33 and Leu33 platelets. Both under static and flow conditions, Pro33 platelets exhibited a significantly higher Src and FAK activities than Leu33 platelets. Interestingly, even in the absence of the αIIbβ3-fibrinogen interaction, we could detect a shear-induced integrin-mediated signaling of Src and FAK in platelets. In parallel experiments in which platelets were pretreated with abciximab, an integrin αIIbβ3 antagonist, activation of both kinases by shear was inhibited. Conclusion Taken together, our data indicates an important role of αIIbβ3 and shows that Leu33Pro polymorphism modulates the integrin-mediated Src and FAK signaling in platelets in response to shear stress. |
| Databáze: | OpenAIRE |
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