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Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity

BACKGROUND: Several genome-wide association studies have reported a risk locus for coronary artery disease (CAD) in the 9p21. 3 chromosomal region. This region encodes a lncRNA in the INK4 locus (ANRIL) and its genetic variance has a strong association with CAD, but its mechanisms in atherogenesis r...

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Autores principales: Kettunen, Sanna, Ruotsalainen, Anna-Kaisa, Örd, Tiit, Suoranta, Tuisku, Heikkilä, Janne, Kaikkonen, Minna U., Laham-Karam, Nihay, Ylä-Herttuala, Seppo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025322/
https://www.ncbi.nlm.nih.gov/pubmed/36950286
http://dx.doi.org/10.3389/fcvm.2023.1113890
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author Kettunen, Sanna
Ruotsalainen, Anna-Kaisa
Örd, Tiit
Suoranta, Tuisku
Heikkilä, Janne
Kaikkonen, Minna U.
Laham-Karam, Nihay
Ylä-Herttuala, Seppo
author_facet Kettunen, Sanna
Ruotsalainen, Anna-Kaisa
Örd, Tiit
Suoranta, Tuisku
Heikkilä, Janne
Kaikkonen, Minna U.
Laham-Karam, Nihay
Ylä-Herttuala, Seppo
author_sort Kettunen, Sanna
collection PubMed
description BACKGROUND: Several genome-wide association studies have reported a risk locus for coronary artery disease (CAD) in the 9p21. 3 chromosomal region. This region encodes a lncRNA in the INK4 locus (ANRIL) and its genetic variance has a strong association with CAD, but its mechanisms in atherogenesis remain unclear. OBJECTIVES: This study aimed to investigate the role of the murine ortholog of human 9p21.3 locus in atherogenesis in hypercholesterolemic mice. METHODS: Murine 9p21.3 ortholog knockout mice (Chr4(Δ70kb/Δ70kb)) were crossbred with Ldlr(−/−)ApoB(100/100) mice, and atherosclerotic plaque size and morphology were analyzed on a standard or a high-fat diet (HFD). The hematopoietic cell-specific effect of Chr4(Δ70kb/Δ70kb) on atherosclerotic plaque development was studied via bone marrow (BM) transplantation, where Chr4(Δ70kb/Δ70kb) or wild-type BM was transplanted into Ldlr(−/−)ApoB(100/100) mice. The role of Chr4(Δ70kb/Δ70kb) in macrophage M1/M2 polarization was studied. In addition, single-cell sequencing data from human and mouse atheroma were analyzed to show the expression profiles of ANRIL and its murine equivalent, Ak148321, in the plaques. RESULTS: Both systemic and hematopoietic Chr4(Δ70kb/Δ70kb) increased atherosclerosis in Ldlr(−/−)ApoB(100/100) mice after 12 weeks of HFD. The systemic Chr4(Δ70kb/Δ70kb) also elevated the number of circulating leukocytes. Chr4(Δ70kb/Δ70kb) BMDMs showed enhanced M1 polarization in vitro. Single-cell sequencing data from human and mouse atheroma revealed that ANRIL and Ak148321 were mainly expressed in the immune cells. CONCLUSION: These data demonstrate that both systemic and BM-specific deletion of the murine 9p21.3 risk locus ortholog promotes atherosclerosis and regulates macrophage pro-inflammatory activity, suggesting the inflammation-driven mechanisms of the risk locus on atherogenesis.
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spelling pubmed-100253222023-03-21 Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity Kettunen, Sanna Ruotsalainen, Anna-Kaisa Örd, Tiit Suoranta, Tuisku Heikkilä, Janne Kaikkonen, Minna U. Laham-Karam, Nihay Ylä-Herttuala, Seppo Front Cardiovasc Med Cardiovascular Medicine BACKGROUND: Several genome-wide association studies have reported a risk locus for coronary artery disease (CAD) in the 9p21. 3 chromosomal region. This region encodes a lncRNA in the INK4 locus (ANRIL) and its genetic variance has a strong association with CAD, but its mechanisms in atherogenesis remain unclear. OBJECTIVES: This study aimed to investigate the role of the murine ortholog of human 9p21.3 locus in atherogenesis in hypercholesterolemic mice. METHODS: Murine 9p21.3 ortholog knockout mice (Chr4(Δ70kb/Δ70kb)) were crossbred with Ldlr(−/−)ApoB(100/100) mice, and atherosclerotic plaque size and morphology were analyzed on a standard or a high-fat diet (HFD). The hematopoietic cell-specific effect of Chr4(Δ70kb/Δ70kb) on atherosclerotic plaque development was studied via bone marrow (BM) transplantation, where Chr4(Δ70kb/Δ70kb) or wild-type BM was transplanted into Ldlr(−/−)ApoB(100/100) mice. The role of Chr4(Δ70kb/Δ70kb) in macrophage M1/M2 polarization was studied. In addition, single-cell sequencing data from human and mouse atheroma were analyzed to show the expression profiles of ANRIL and its murine equivalent, Ak148321, in the plaques. RESULTS: Both systemic and hematopoietic Chr4(Δ70kb/Δ70kb) increased atherosclerosis in Ldlr(−/−)ApoB(100/100) mice after 12 weeks of HFD. The systemic Chr4(Δ70kb/Δ70kb) also elevated the number of circulating leukocytes. Chr4(Δ70kb/Δ70kb) BMDMs showed enhanced M1 polarization in vitro. Single-cell sequencing data from human and mouse atheroma revealed that ANRIL and Ak148321 were mainly expressed in the immune cells. CONCLUSION: These data demonstrate that both systemic and BM-specific deletion of the murine 9p21.3 risk locus ortholog promotes atherosclerosis and regulates macrophage pro-inflammatory activity, suggesting the inflammation-driven mechanisms of the risk locus on atherogenesis. Frontiers Media S.A. 2023-03-06 /pmc/articles/PMC10025322/ /pubmed/36950286 http://dx.doi.org/10.3389/fcvm.2023.1113890 Text en Copyright © 2023 Kettunen, Ruotsalainen, Örd, Suoranta, Heikkilä, Kaikkonen, Laham-Karam and Ylä-Herttuala. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Kettunen, Sanna
Ruotsalainen, Anna-Kaisa
Örd, Tiit
Suoranta, Tuisku
Heikkilä, Janne
Kaikkonen, Minna U.
Laham-Karam, Nihay
Ylä-Herttuala, Seppo
Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
title Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
title_full Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
title_fullStr Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
title_full_unstemmed Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
title_short Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
title_sort deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025322/
https://www.ncbi.nlm.nih.gov/pubmed/36950286
http://dx.doi.org/10.3389/fcvm.2023.1113890
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