Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity
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2023Author(s)
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10.3389/fcvm.2023.1113890Metadata
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Kettunen, Sanna. Ruotsalainen, Anna-Kaisa. Örd, Tiit. Suoranta, Tuisku. Heikkilä, Janne. Kaikkonen, Minna U.. Laham-Karam, Nihay. Ylä-Herttuala, Seppo. (2023). Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity. Frontiers in cardiovascular medicine, 10, 1113890. 10.3389/fcvm.2023.1113890.Rights
Abstract
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 (Chr4Δ70kb/Δ70kb) were crossbred with Ldlr−/−ApoB100/100 mice, and atherosclerotic plaque size and morphology were analyzed on a standard or a high-fat diet (HFD). The hematopoietic cell-specific effect of Chr4Δ70kb/Δ70kb on atherosclerotic plaque development was studied via bone marrow (BM) transplantation, where Chr4Δ70kb/Δ70kb or wild-type BM was transplanted into Ldlr−/−ApoB100/100 mice. The role of Chr4Δ70kb/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 Chr4Δ70kb/Δ70kb increased atherosclerosis in Ldlr−/−ApoB100/100 mice after 12 weeks of HFD. The systemic Chr4Δ70kb/Δ70kb also elevated the number of circulating leukocytes. Chr4Δ70kb/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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https://doi.org/10.3389/fcvm.2023.1113890Publisher
Frontiers Media S.ACollections
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