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.

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

Sanguinetti C.;Pedrinelli R.;Celi A.;Neri T.
2022-01-01

Abstract

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.
2022
Scalise, V.; Lombardi, S.; Sanguinetti, C.; Nieri, D.; Pedrinelli, R.; Celi, A.; Neri, T.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1160357
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