Background: Extracellular vesicles (EV) concentration is generally increased in patients with cardiovascular diseases, although the protective role of EVs in atherosclerosis has been reported. Among the specific cargo of EVs, miRNAs contribute to different stages of atherosclerosis. Aim of the present report has been to investigate, in individuals with obesity, the interplay among EVs derived from cells relevant for the atherosclerotic process (i.e., platelets, endothelium, monocytes/macrophages, and neutrophils), their miRNA content and proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of low-density lipoprotein receptor (LDLR). Methods and Results: EVs have been isolated from 936 individuals with obesity (body mass index = 33.6 ± 5.6 Kg/m2) and a raised cardiovascular risk (e.g., LDL-C = 131.6 ± 36.4 mg/dL, HOMA-IR = 3.1, and roughly 50% on anti-hypertensive medications). PCSK9 levels were negatively associated with EV count in the range 150–400 nm and with those derived from macrophages (CD14+), endothelium (CD105+), and neutrophils (CD66+). The association between PCSK9 and platelet-derived EVs (CD61+) was modified by platelet counts. PCSK9 was significantly associated with five EV-derived miRNAs (hsa-miRNA−362−5p,−150,−1244,−520b-3p,−638). Toll-like receptor 4 and estrogen receptor 1 were targeted by all five miRNAs and LDLR by four. The effect on LDLR expression is mainly driven by hsa-miR-150. Considering the implication of EV in atherosclerosis onset and progression, our findings show a potential role of PCSK9 to regulate EV-derived miRNAs, especially those involved in inflammation and expression of low-density lipoprotein receptor (LDLR) receptor.

Associations Among PCSK9 Levels, Atherosclerosis-Derived Extracellular Vesicles, and Their miRNA Content in Adults With Obesity / C. Macchi, M.F. Greco, C. Favero, L. Dioni, L. Cantone, M. Hoxha, L. Vigna, G. Solazzo, A. Corsini, M. Banach, A.C. Pesatori, V. Bollati, M. Ruscica. - In: FRONTIERS IN CARDIOVASCULAR MEDICINE. - ISSN 2297-055X. - 8:(2022), pp. 1-11. [10.3389/fcvm.2021.785250]

Associations Among PCSK9 Levels, Atherosclerosis-Derived Extracellular Vesicles, and Their miRNA Content in Adults With Obesity

C. Macchi
Co-primo
Writing – Original Draft Preparation
;
M.F. Greco
Co-primo
Writing – Original Draft Preparation
;
C. Favero
Data Curation
;
L. Dioni
Methodology
;
L. Cantone
Methodology
;
M. Hoxha
Methodology
;
L. Vigna
Investigation
;
G. Solazzo
Methodology
;
A. Corsini
Writing – Review & Editing
;
A.C. Pesatori
Writing – Review & Editing
;
V. Bollati
Penultimo
Writing – Review & Editing
;
M. Ruscica
Ultimo
Writing – Review & Editing
2022

Abstract

Background: Extracellular vesicles (EV) concentration is generally increased in patients with cardiovascular diseases, although the protective role of EVs in atherosclerosis has been reported. Among the specific cargo of EVs, miRNAs contribute to different stages of atherosclerosis. Aim of the present report has been to investigate, in individuals with obesity, the interplay among EVs derived from cells relevant for the atherosclerotic process (i.e., platelets, endothelium, monocytes/macrophages, and neutrophils), their miRNA content and proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of low-density lipoprotein receptor (LDLR). Methods and Results: EVs have been isolated from 936 individuals with obesity (body mass index = 33.6 ± 5.6 Kg/m2) and a raised cardiovascular risk (e.g., LDL-C = 131.6 ± 36.4 mg/dL, HOMA-IR = 3.1, and roughly 50% on anti-hypertensive medications). PCSK9 levels were negatively associated with EV count in the range 150–400 nm and with those derived from macrophages (CD14+), endothelium (CD105+), and neutrophils (CD66+). The association between PCSK9 and platelet-derived EVs (CD61+) was modified by platelet counts. PCSK9 was significantly associated with five EV-derived miRNAs (hsa-miRNA−362−5p,−150,−1244,−520b-3p,−638). Toll-like receptor 4 and estrogen receptor 1 were targeted by all five miRNAs and LDLR by four. The effect on LDLR expression is mainly driven by hsa-miR-150. Considering the implication of EV in atherosclerosis onset and progression, our findings show a potential role of PCSK9 to regulate EV-derived miRNAs, especially those involved in inflammation and expression of low-density lipoprotein receptor (LDLR) receptor.
therosclerosis; PCSK9 (proprotein convertase subtilisin kexin type 9); extracellular vesicles (EVs); miR-150; obesity; low-density lipoprotein receptor (LDLR)
Settore MED/04 - Patologia Generale
Settore BIO/14 - Farmacologia
Settore MED/44 - Medicina del Lavoro
2022
7-gen-2022
Article (author)
File in questo prodotto:
File Dimensione Formato  
Chiara Macchi.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.09 MB
Formato Adobe PDF
1.09 MB Adobe PDF Visualizza/Apri
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/2434/894622
Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 13
social impact