Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization
We have previously shown that third-generation antisense (3GA) inhibition of 14q32 microRNA (miRNA)-494 reduced early development of atherosclerosis. However, patients at risk of atherosclerotic complications generally present with advanced and unstable lesions. Here, we administered 3GAs against 14...
| 主要な著者: | , , , , , , |
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| フォーマット: | 論文 |
| 言語: | English |
| 出版事項: |
Elsevier
2019-12-01
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| シリーズ: | Molecular Therapy: Nucleic Acids |
| オンライン･アクセス: | http://www.sciencedirect.com/science/article/pii/S2162253119302689 |
| _version_ | 1830345266917539840 |
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| author | Eva van Ingen Amanda C. Foks Mara J. Kröner Johan Kuiper Paul H.A. Quax Ilze Bot Anne Yaël Nossent |
| author_facet | Eva van Ingen Amanda C. Foks Mara J. Kröner Johan Kuiper Paul H.A. Quax Ilze Bot Anne Yaël Nossent |
| author_sort | Eva van Ingen |
| collection | DOAJ |
| description | We have previously shown that third-generation antisense (3GA) inhibition of 14q32 microRNA (miRNA)-494 reduced early development of atherosclerosis. However, patients at risk of atherosclerotic complications generally present with advanced and unstable lesions. Here, we administered 3GAs against 14q32 miRNA-494 (3GA-494), miRNA-329 (3GA-329), or a control (3GA-ctrl) to mice with advanced atherosclerosis. Atherosclerotic plaque formation in LDLr−/− mice was induced by a 10-week high-fat diet and simultaneous carotid artery collar placement. Parallel to 3GA-treatment, hyperlipidemia was normalized by a diet switch to regular chow for an additional 5 weeks. We show that, even though plasma cholesterol levels were normalized after diet switch, carotid artery plaque progression continued in 3GA-ctrl mice. However, treatment with 3GA-494 and, in part, 3GA-329 halted plaque progression. Furthermore, in the aortic root, intra-plaque collagen content was increased in 3GA-494 mice, accompanied by a reduction in the intra-plaque macrophage content. Pro-atherogenic cells in the circulation, including inflammatory Ly6Chi monocytes, neutrophils, and blood platelets, were decreased upon miRNA-329 and miRNA-494 inhibition. Taken together, treatment with 3GA-494, and in part with 3GA-329, halts atherosclerotic plaque progression and promotes stabilization of advanced lesions, which is highly relevant for human atherosclerosis. |
| first_indexed | 2024-12-19T22:40:08Z |
| format | Article |
| id | doaj.art-c0ecfbcecf4a4e57b8835ececd858d65 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-19T22:40:08Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-c0ecfbcecf4a4e57b8835ececd858d652022-12-21T20:03:05ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-12-0118638649Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque StabilizationEva van Ingen0Amanda C. Foks1Mara J. Kröner2Johan Kuiper3Paul H.A. Quax4Ilze Bot5Anne Yaël Nossent6Department of Surgery, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC, Leiden, the NetherlandsDivision BioTherapeutics, LACDR, Leiden University, 2333 CC, Leiden, the NetherlandsDivision BioTherapeutics, LACDR, Leiden University, 2333 CC, Leiden, the NetherlandsDivision BioTherapeutics, LACDR, Leiden University, 2333 CC, Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC, Leiden, the NetherlandsDivision BioTherapeutics, LACDR, Leiden University, 2333 CC, Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands; Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Corresponding author: Anne Yaël Nossent, Department of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands.We have previously shown that third-generation antisense (3GA) inhibition of 14q32 microRNA (miRNA)-494 reduced early development of atherosclerosis. However, patients at risk of atherosclerotic complications generally present with advanced and unstable lesions. Here, we administered 3GAs against 14q32 miRNA-494 (3GA-494), miRNA-329 (3GA-329), or a control (3GA-ctrl) to mice with advanced atherosclerosis. Atherosclerotic plaque formation in LDLr−/− mice was induced by a 10-week high-fat diet and simultaneous carotid artery collar placement. Parallel to 3GA-treatment, hyperlipidemia was normalized by a diet switch to regular chow for an additional 5 weeks. We show that, even though plasma cholesterol levels were normalized after diet switch, carotid artery plaque progression continued in 3GA-ctrl mice. However, treatment with 3GA-494 and, in part, 3GA-329 halted plaque progression. Furthermore, in the aortic root, intra-plaque collagen content was increased in 3GA-494 mice, accompanied by a reduction in the intra-plaque macrophage content. Pro-atherogenic cells in the circulation, including inflammatory Ly6Chi monocytes, neutrophils, and blood platelets, were decreased upon miRNA-329 and miRNA-494 inhibition. Taken together, treatment with 3GA-494, and in part with 3GA-329, halts atherosclerotic plaque progression and promotes stabilization of advanced lesions, which is highly relevant for human atherosclerosis.http://www.sciencedirect.com/science/article/pii/S2162253119302689 |
| spellingShingle | Eva van Ingen Amanda C. Foks Mara J. Kröner Johan Kuiper Paul H.A. Quax Ilze Bot Anne Yaël Nossent Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization Molecular Therapy: Nucleic Acids |
| title | Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization |
| title_full | Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization |
| title_fullStr | Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization |
| title_full_unstemmed | Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization |
| title_short | Antisense Oligonucleotide Inhibition of MicroRNA-494 Halts Atherosclerotic Plaque Progression and Promotes Plaque Stabilization |
| title_sort | antisense oligonucleotide inhibition of microrna 494 halts atherosclerotic plaque progression and promotes plaque stabilization |
| url | http://www.sciencedirect.com/science/article/pii/S2162253119302689 |
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