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Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways

Authors :
Vittoria Cammisotto
Francesco Baratta
Valentina Castellani
Simona Bartimoccia
Cristina Nocella
Laura D’Erasmo
Nicholas Cocomello
Cristina Barale
Roberto Scicali
Antonino Di Pino
Salvatore Piro
Maria Del Ben
Marcello Arca
Isabella Russo
Francesco Purrello
Roberto Carnevale
Francesco Violi
Daniele Pastori
Pasquale Pignatelli
Source :
International Journal of Molecular Sciences, Vol 22, Iss 13, p 7193 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before–after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
22
Issue :
13
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.171573ddc71f416aae5ccf938bf88c30
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms22137193