PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo.

Sai Sahana Sundararaman,Linsey J F Peters,Andrea Bonnin Marquez,Soyolmaa Bayasgalan,Emiel P C Van Der Vorst,Janneke E Bouma,Sumra Nazir,Yvonne Döring

doi:10.3390/ijms222313026

Abstract

Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.

Highlights

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease mainly secreted by the liver and has been extensively studied as a focal player in lipid metabolism [1]
In this study, we aimed to investigate whether PCSK9 influences the expression of selected chemokine receptors as well as cytokines that are well known to participate in atherosclerosis and other cardiovascular complications (CXCR4, CCR8, CCR5, and CCR2) in in vitro and in vivo models, which could unveil a novel approach to modulate vascular inflammation
The expression in the chemokine receptors CXCR4, CCR8, CCR5, and CCR2, which are all known to play an important role in inflammation and atherosclerosis development [24,25,26,27,28,29,30,31], was analyzed on the surface of various leukocyte subsets in the blood (Figure 1) and spleen (Figure 2) using flow cytometry

Summary

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease mainly secreted by the liver and has been extensively studied as a focal player in lipid metabolism [1]. PCSK9 binds to the low-density lipoprotein receptor (LDLR), causing the lysosomal degradation of the receptor. As this receptor mediates the clearance of LDL-cholesterol (LDL-C), its degradation causes an increase in circulating cholesterol levels [2]. In this context, major efforts over the last years have resulted in the clinical application of anti-PCSK9 antibodies to reduce circulating lipid levels and thereby the risk for cardiovascular disease [3,4,5]. Circulating PCSK9 has effects on platelet reactivity [14], Apolipoprotein E receptor 2 (ApoER2) [15], and Cluster of differentiation 36 (CD36) [16]

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Conclusion