Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players

Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular...

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Autores principales:	Patrice Marques, Elena Domingo, Arantxa Rubio, Sergio Martinez-Hervás, Juan F. Ascaso, Laura Piqueras, José T. Real, Maria-Jesus Sanz
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Familial hypercholesterolemia PCSK9 Alirocumab Systemic inflammation Endothelial dysfunction Atherosclerosis Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/18b9bb9d7ffb44ad935d98f1e616d8cd
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spelling	oai:doaj.org-article:18b9bb9d7ffb44ad935d98f1e616d8cd2021-12-02T04:59:06ZBeneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players0753-332210.1016/j.biopha.2021.112460https://doaj.org/article/18b9bb9d7ffb44ad935d98f1e616d8cd2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012464https://doaj.org/toc/0753-3322Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular outcomes in patients with FH. Fourteen patients with FH were evaluated before and 8 weeks after administration of a PCSK9 blocking monoclonal antibody (alirocumab, 150 mg/subcutaneous/14 days). In vivo and ex vivo analysis revealed that alirocumab blunted the attachment of leukocytes to TNFα-stimulated human umbilical arterial endothelial cells (HUAEC) and suppressed the activation of platelets and most leukocyte subsets, which was accompanied by the diminished expression of CX3CR1, CXCR6 and CCR2 on several leukocyte subpopulations. By contrast, T-regulatory cell activation was enhanced by alirocumab treatment, which also elevated anti-inflammatory IL-10 plasma levels and lowered circulating pro-inflammatory cytokines. Plasma levels of IFNγ positively correlated with levels of total and LDL-cholesterol, whereas circulating IL-10 levels negatively correlated with these key lipid parameters. In vitro analysis revealed that TNFα stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNFα-induced mononuclear cell adhesion mediated by Nox5 up-regulation and p38-MAPK/NFκB activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CX3CL1 and CXCL16 expression and chemokine generation. In conclusion, PCSK9 inhibition impairs systemic inflammation and endothelial dysfunction by constraining leukocyte-endothelium interactions. PCSK9 blockade may constitute a new therapeutic approach to control the inflammatory state associated with FH, preventing further cardiovascular events in this cardiometabolic disorder.Patrice MarquesElena DomingoArantxa RubioSergio Martinez-HervásJuan F. AscasoLaura PiquerasJosé T. RealMaria-Jesus SanzElsevierarticleFamilial hypercholesterolemiaPCSK9AlirocumabSystemic inflammationEndothelial dysfunctionAtherosclerosisTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112460- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Familial hypercholesterolemia PCSK9 Alirocumab Systemic inflammation Endothelial dysfunction Atherosclerosis Therapeutics. Pharmacology RM1-950
spellingShingle	Familial hypercholesterolemia PCSK9 Alirocumab Systemic inflammation Endothelial dysfunction Atherosclerosis Therapeutics. Pharmacology RM1-950 Patrice Marques Elena Domingo Arantxa Rubio Sergio Martinez-Hervás Juan F. Ascaso Laura Piqueras José T. Real Maria-Jesus Sanz Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
description	Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular outcomes in patients with FH. Fourteen patients with FH were evaluated before and 8 weeks after administration of a PCSK9 blocking monoclonal antibody (alirocumab, 150 mg/subcutaneous/14 days). In vivo and ex vivo analysis revealed that alirocumab blunted the attachment of leukocytes to TNFα-stimulated human umbilical arterial endothelial cells (HUAEC) and suppressed the activation of platelets and most leukocyte subsets, which was accompanied by the diminished expression of CX3CR1, CXCR6 and CCR2 on several leukocyte subpopulations. By contrast, T-regulatory cell activation was enhanced by alirocumab treatment, which also elevated anti-inflammatory IL-10 plasma levels and lowered circulating pro-inflammatory cytokines. Plasma levels of IFNγ positively correlated with levels of total and LDL-cholesterol, whereas circulating IL-10 levels negatively correlated with these key lipid parameters. In vitro analysis revealed that TNFα stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNFα-induced mononuclear cell adhesion mediated by Nox5 up-regulation and p38-MAPK/NFκB activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CX3CL1 and CXCL16 expression and chemokine generation. In conclusion, PCSK9 inhibition impairs systemic inflammation and endothelial dysfunction by constraining leukocyte-endothelium interactions. PCSK9 blockade may constitute a new therapeutic approach to control the inflammatory state associated with FH, preventing further cardiovascular events in this cardiometabolic disorder.
format	article
author	Patrice Marques Elena Domingo Arantxa Rubio Sergio Martinez-Hervás Juan F. Ascaso Laura Piqueras José T. Real Maria-Jesus Sanz
author_facet	Patrice Marques Elena Domingo Arantxa Rubio Sergio Martinez-Hervás Juan F. Ascaso Laura Piqueras José T. Real Maria-Jesus Sanz
author_sort	Patrice Marques
title	Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
title_short	Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
title_full	Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
title_fullStr	Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
title_full_unstemmed	Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
title_sort	beneficial effects of pcsk9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/18b9bb9d7ffb44ad935d98f1e616d8cd
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Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players

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