Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells / M.F. Greco, A.S. Rizzuto, M. Zarà, M. Cafora, C. Favero, G. Solazzo, I. Giusti, M.P. Adorni, F. Zimetti, V. Dolo, C. Banfi, N. Ferri, C.R. Sirtori, A. Corsini, S.S. Barbieri, A. Pistocchi, V. Bollati, C. Macchi, M. Ruscica. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 23:21(2022), pp. 13065.1-13065.26. [10.3390/ijms232113065]

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells

M.F. Greco
Primo
Writing – Original Draft Preparation
;
A.S. Rizzuto
Secondo
Methodology
;
M. Cafora
Methodology
;
C. Favero
Methodology
;
G. Solazzo
Methodology
;
A. Corsini
Writing – Review & Editing
;
A. Pistocchi
Writing – Review & Editing
;
V. Bollati
Writing – Review & Editing
;
C. Macchi
Penultimo
Writing – Review & Editing
;
M. Ruscica
Ultimo
Writing – Review & Editing
2022

Abstract

Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.
PCSK9; atherosclerosis; extracellular vesicles; inflammation; vascular smooth muscle cells.
Settore MED/04 - Patologia Generale
Settore BIO/14 - Farmacologia
Settore BIO/13 - Biologia Applicata
Settore MED/44 - Medicina del Lavoro
CAR_RIC19EMARC_01 - Deciphering the role of ADAM10 and CAP2 in Age‐related Accumulation of deficits - MARCELLO, ELENA - CAR_RIC - Bandi Fondazione Cariplo - 2019
Article (author)
File in questo prodotto:
File Dimensione Formato  
ijms-23-13065(7)-2_compressed-2.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 558.87 kB
Formato Adobe PDF
558.87 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/945321
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact