Article ; Online: The Subtilisin-Like Protease Furin Regulates Hemin-Dependent Ectodomain Shedding of Glycoprotein VI.
2023 Volume 123, Issue 7, Page(s) 679–691
Abstract: Introduction: Hemolysis results in release of free hemoglobin and hemin liberation from erythrocytes. Hemin has been described to induce platelet activation and to trigger thrombosis.: Methods: We evaluated the effect of hemin on platelet function ... ...
| Abstract | Introduction: Hemolysis results in release of free hemoglobin and hemin liberation from erythrocytes. Hemin has been described to induce platelet activation and to trigger thrombosis. Methods: We evaluated the effect of hemin on platelet function and surface expression of the platelet collagen receptor glycoprotein VI (GPVI). Isolated platelets were stimulated with increasing concentrations of hemin. Results: We found that hemin strongly enhanced platelet activation, aggregation, and aggregate formation on immobilized collagen under flow. In contrast, we found that surface expression of GPVI was significantly reduced upon hemin stimulation with high hemin concentrations indicating that hemin-induced loss of surface GPVI does not hinder platelet aggregation. Loss of hemin-induced surface expression of GPVI was caused by shedding of the ectodomain of GPVI as verified by immunoblotting and is independent of the GPVI or CLEC-2 mediated ITAM (immunoreceptor-tyrosine-based-activation-motif) signaling pathway as inhibitor studies revealed. Hemin-induced GPVI shedding was independent of metalloproteinases such as ADAM10 or ADAM17, which were previously described to regulate GPVI degradation. Similarly, concentration-dependent shedding of CD62P was also induced by hemin. Unexpectedly, we found that the subtilisin-like proprotein convertase furin controls hemin-dependent GPVI shedding as shown by inhibitor studies using the specific furin inhibitors SSM3 and Hexa-D-arginine. In the presence of SSM3 and Hexa-D-arginine, hemin-associated GPVI degradation was substantially reduced. Further, SSM3 inhibited hemin-induced but not CRP-XL-induced platelet aggregation and thrombus formation, indicating that furin controls specifically hemin-associated platelet functions. Conclusion: In summary, we describe a novel mechanism of hemin-dependent GPVI shedding and platelet function mediated by furin. |
|---|---|
| MeSH term(s) | Humans ; Hemin/pharmacology ; Hemin/metabolism ; Furin/metabolism ; Furin/pharmacology ; Platelet Membrane Glycoproteins/metabolism ; Blood Platelets/metabolism ; Platelet Aggregation ; Platelet Activation |
| Chemical Substances | Hemin (743LRP9S7N) ; Furin (EC 3.4.21.75) ; Platelet Membrane Glycoproteins |
| Language | English |
| Publishing date | 2023-04-10 |
| Publishing country | Germany |
| Document type | Journal Article |
| ZDB-ID | 518294-3 |
| ISSN | 2567-689X ; 0340-6245 |
| ISSN (online) | 2567-689X |
| ISSN | 0340-6245 |
| DOI | 10.1055/s-0043-1768057 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Uh III Zs.192: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
|||
| Zs.MO 433: Show issues |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.