Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis

We have previously shown that treatment with third-generation antisense oligonucleotides against miR-494-3p (3GA-494) reduces atherosclerotic plaque progression and stabilizes lesions, both in early and established plaques, with reduced macrophage content in established plaques. Within the plaque, d...

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Autores principales:	Eva van Ingen, Amanda C. Foks, Tamar Woudenberg, M. Leontien van der Bent, Alwin de Jong, Philipp J. Hohensinner, Johann Wojta, Ilze Bot, Paul.H.A. Quax, Anne Yaël Nossent
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	microRNA-494-3p 14q32 locus DLK1-DIO3 locus antisense oligonucleotides macrophage polarization atherosclerosis Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3c732ba897314891bf7651163691b08a
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spelling	oai:doaj.org-article:3c732ba897314891bf7651163691b08a2021-11-20T05:05:34ZInhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis2162-253110.1016/j.omtn.2021.10.027https://doaj.org/article/3c732ba897314891bf7651163691b08a2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2162253121002705https://doaj.org/toc/2162-2531We have previously shown that treatment with third-generation antisense oligonucleotides against miR-494-3p (3GA-494) reduces atherosclerotic plaque progression and stabilizes lesions, both in early and established plaques, with reduced macrophage content in established plaques. Within the plaque, different subtypes of macrophages are present. Here, we aimed to investigate whether miR-494-3p directly influences macrophage polarization and activation. Human macrophages were polarized into either proinflammatory M1 or anti-inflammatory M2 macrophages and simultaneously treated with 3GA-494 or a control antisense (3GA-ctrl). We show that 3GA-494 treatment inhibited miR-494-3p in M1 macrophages and dampened M1 polarization, while in M2 macrophages miR-494-3p expression was induced and M2 polarization enhanced. The proinflammatory marker CCR2 was reduced in 3GA-494-treated atherosclerosis-prone mice. Pathway enrichment analysis predicted an overlap between miR-494-3p target genes in macrophage polarization and Wnt signaling. We demonstrate that miR-494-3p regulates expression levels of multiple Wnt signaling components, such as LRP6 and TBL1X. Wnt signaling appears activated upon treatment with 3GA-494, both in cultured M1 macrophages and in plaques of hypercholesterolemic mice. Taken together, 3GA-494 treatment dampened M1 polarization, at least in part via activated Wnt signaling, while M2 polarization was enhanced, which is both favorable in reducing atherosclerotic plaque formation and increasing plaque stability.Eva van IngenAmanda C. FoksTamar WoudenbergM. Leontien van der BentAlwin de JongPhilipp J. HohensinnerJohann WojtaIlze BotPaul.H.A. QuaxAnne Yaël NossentElsevierarticlemicroRNA-494-3p14q32 locusDLK1-DIO3 locusantisense oligonucleotidesmacrophage polarizationatherosclerosisTherapeutics. PharmacologyRM1-950ENMolecular Therapy: Nucleic Acids, Vol 26, Iss , Pp 1228-1239 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	microRNA-494-3p 14q32 locus DLK1-DIO3 locus antisense oligonucleotides macrophage polarization atherosclerosis Therapeutics. Pharmacology RM1-950
spellingShingle	microRNA-494-3p 14q32 locus DLK1-DIO3 locus antisense oligonucleotides macrophage polarization atherosclerosis Therapeutics. Pharmacology RM1-950 Eva van Ingen Amanda C. Foks Tamar Woudenberg M. Leontien van der Bent Alwin de Jong Philipp J. Hohensinner Johann Wojta Ilze Bot Paul.H.A. Quax Anne Yaël Nossent Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
description	We have previously shown that treatment with third-generation antisense oligonucleotides against miR-494-3p (3GA-494) reduces atherosclerotic plaque progression and stabilizes lesions, both in early and established plaques, with reduced macrophage content in established plaques. Within the plaque, different subtypes of macrophages are present. Here, we aimed to investigate whether miR-494-3p directly influences macrophage polarization and activation. Human macrophages were polarized into either proinflammatory M1 or anti-inflammatory M2 macrophages and simultaneously treated with 3GA-494 or a control antisense (3GA-ctrl). We show that 3GA-494 treatment inhibited miR-494-3p in M1 macrophages and dampened M1 polarization, while in M2 macrophages miR-494-3p expression was induced and M2 polarization enhanced. The proinflammatory marker CCR2 was reduced in 3GA-494-treated atherosclerosis-prone mice. Pathway enrichment analysis predicted an overlap between miR-494-3p target genes in macrophage polarization and Wnt signaling. We demonstrate that miR-494-3p regulates expression levels of multiple Wnt signaling components, such as LRP6 and TBL1X. Wnt signaling appears activated upon treatment with 3GA-494, both in cultured M1 macrophages and in plaques of hypercholesterolemic mice. Taken together, 3GA-494 treatment dampened M1 polarization, at least in part via activated Wnt signaling, while M2 polarization was enhanced, which is both favorable in reducing atherosclerotic plaque formation and increasing plaque stability.
format	article
author	Eva van Ingen Amanda C. Foks Tamar Woudenberg M. Leontien van der Bent Alwin de Jong Philipp J. Hohensinner Johann Wojta Ilze Bot Paul.H.A. Quax Anne Yaël Nossent
author_facet	Eva van Ingen Amanda C. Foks Tamar Woudenberg M. Leontien van der Bent Alwin de Jong Philipp J. Hohensinner Johann Wojta Ilze Bot Paul.H.A. Quax Anne Yaël Nossent
author_sort	Eva van Ingen
title	Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
title_short	Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
title_full	Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
title_fullStr	Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
title_full_unstemmed	Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
title_sort	inhibition of microrna-494-3p activates wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/3c732ba897314891bf7651163691b08a
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Inhibition of microRNA-494-3p activates Wntsignaling and reduces proinflammatorymacrophage polarization in atherosclerosis

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