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A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells

BACKGROUND: Proprotein convertase subtilisin kexin 9 (PCSK9) is a serin protease synthesized mainly in the liver that binds the receptor of low-density lipoprotein and promotes its degradation in lysosomes. PCSK9 is considered a promising target for the development of new therapies for the treatment...

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Autores principales: Scalise, Valentina, Lombardi, Stefania, Sanguinetti, Chiara, Nieri, Dario, Pedrinelli, Roberto, Celi, Alessandro, Neri, Tommaso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9001820/
https://www.ncbi.nlm.nih.gov/pubmed/35412175
http://dx.doi.org/10.1007/s11033-022-07433-x
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author Scalise, Valentina
Lombardi, Stefania
Sanguinetti, Chiara
Nieri, Dario
Pedrinelli, Roberto
Celi, Alessandro
Neri, Tommaso
author_facet Scalise, Valentina
Lombardi, Stefania
Sanguinetti, Chiara
Nieri, Dario
Pedrinelli, Roberto
Celi, Alessandro
Neri, Tommaso
author_sort Scalise, Valentina
collection PubMed
description BACKGROUND: Proprotein convertase subtilisin kexin 9 (PCSK9) is a serin protease synthesized mainly in the liver that binds the receptor of low-density lipoprotein and promotes its degradation in lysosomes. PCSK9 is considered a promising target for the development of new therapies for the treatment of hypercholesterolemia and related cardiovascular diseases. Extracellular vesicles represent a heterogeneous population of vesicles, ranging in size between 0.05 and 1 μm involved in numerous pathophysiological processes, including blood coagulation. We investigated whether PCSK9 stimulation induces the release of procoagulant extracellular vesicles from human mononuclear cells (PBMCs) and THP-1 cells. METHODS AND RESULTS: PBMCs and THP-1 cells were stimulated whit PCSK9, the generation of EV was assessed by the prothrombinase assay and by cytofluorimetric analysis. EV-associated tissue factor activity was assessed by a one-stage clotting assay. PCSK9 induced an increase in extracellular generation by PBMCs and THP-1 cells as well as an increase in extracellular vesicle-associated tissue factor. Pre-treatment with inhibitors of the toll like receptor, TLR4 (C34), and of NF-κB signaling (BAY 11-7082), downregulated PCSK9-induced extracellular vesicle generation and of extracellular- bound tissue factor. Similar effect was obtained by an anti-PCSK9 human-monoclonal antibody. CONCLUSIONS: PCSK9-mediated generation of procoagulant EV could contribute to increase the prothrombotic status in patients with cardiovascular diseases.
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spelling pubmed-90018202022-04-12 A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells Scalise, Valentina Lombardi, Stefania Sanguinetti, Chiara Nieri, Dario Pedrinelli, Roberto Celi, Alessandro Neri, Tommaso Mol Biol Rep Short Communication BACKGROUND: Proprotein convertase subtilisin kexin 9 (PCSK9) is a serin protease synthesized mainly in the liver that binds the receptor of low-density lipoprotein and promotes its degradation in lysosomes. PCSK9 is considered a promising target for the development of new therapies for the treatment of hypercholesterolemia and related cardiovascular diseases. Extracellular vesicles represent a heterogeneous population of vesicles, ranging in size between 0.05 and 1 μm involved in numerous pathophysiological processes, including blood coagulation. We investigated whether PCSK9 stimulation induces the release of procoagulant extracellular vesicles from human mononuclear cells (PBMCs) and THP-1 cells. METHODS AND RESULTS: PBMCs and THP-1 cells were stimulated whit PCSK9, the generation of EV was assessed by the prothrombinase assay and by cytofluorimetric analysis. EV-associated tissue factor activity was assessed by a one-stage clotting assay. PCSK9 induced an increase in extracellular generation by PBMCs and THP-1 cells as well as an increase in extracellular vesicle-associated tissue factor. Pre-treatment with inhibitors of the toll like receptor, TLR4 (C34), and of NF-κB signaling (BAY 11-7082), downregulated PCSK9-induced extracellular vesicle generation and of extracellular- bound tissue factor. Similar effect was obtained by an anti-PCSK9 human-monoclonal antibody. CONCLUSIONS: PCSK9-mediated generation of procoagulant EV could contribute to increase the prothrombotic status in patients with cardiovascular diseases. Springer Netherlands 2022-04-12 2022 /pmc/articles/PMC9001820/ /pubmed/35412175 http://dx.doi.org/10.1007/s11033-022-07433-x Text en © The Author(s), under exclusive licence to Springer Nature B.V. 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Short Communication
Scalise, Valentina
Lombardi, Stefania
Sanguinetti, Chiara
Nieri, Dario
Pedrinelli, Roberto
Celi, Alessandro
Neri, Tommaso
A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
title A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
title_full A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
title_fullStr A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
title_full_unstemmed A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
title_short A novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
title_sort novel prothrombotic role of proprotein convertase subtilisin kexin 9: the generation of procoagulant extracellular vesicles by human mononuclear cells
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9001820/
https://www.ncbi.nlm.nih.gov/pubmed/35412175
http://dx.doi.org/10.1007/s11033-022-07433-x
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