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

Vittoria Cammisotto,Valentina Castellani,Pasquale Pignatelli,Cristina Barale,Nicholas Cocomello,Salvatore Piro,Isabella Russo,Antonino Di Pino,Daniele Pastori,Roberto Carnevale,Simona Bartimoccia,Maria Del Ben,Francesco Purrello,Roberto Scicali,Cristina Nocella,Marcello Arca,Francesco Violi,Laura D’Erasmo,Francesco Baratta

doi:10.3390/ijms22137193

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.

Highlights

Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a key role in lipid metabolism and atherothrombotic process binding low-density lipoprotein cholesterol receptors (LDLRs) and addressing them to lysosomes where they are degraded [1,2]
Prior cardiovascular events were recorded in 51.5% of patients, 41 out of 41 had coronary heart disease and 2 had peripheral artery diseases in addition
None of the patients had diabetes and all the patients were on statin treatment (Table 1)

Summary

Introduction

Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a key role in lipid metabolism and atherothrombotic process binding low-density lipoprotein cholesterol receptors (LDLRs) and addressing them to lysosomes where they are degraded [1,2]. The PCSK9i, alirocumab, and evolocumab, have been shown to improve atherosclerosis [5,6] and prevent cardiovascular events [7,8]. LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. 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. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients

Methods

Results

Conclusion