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Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization
Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The present study assessed the functional contribution of the lncRNA myocardial infarction-associated transcript (MIAT) to atherosclerosis and carotid arter...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570347/ https://www.ncbi.nlm.nih.gov/pubmed/34647815 http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052023 |
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author | Fasolo, Francesca Jin, Hong Winski, Greg Chernogubova, Ekaterina Pauli, Jessica Winter, Hanna Li, Daniel Y. Glukha, Nadiya Bauer, Sabine Metschl, Susanne Wu, Zhiyuan Koschinsky, Marlys L. Reilly, Muredach Pelisek, Jaroslav Kempf, Wolfgang Eckstein, Hans-Henning Soehnlein, Oliver Matic, Ljubica Hedin, Ulf Bäcklund, Alexandra Bergmark, Claes Paloschi, Valentina Maegdefessel, Lars |
author_facet | Fasolo, Francesca Jin, Hong Winski, Greg Chernogubova, Ekaterina Pauli, Jessica Winter, Hanna Li, Daniel Y. Glukha, Nadiya Bauer, Sabine Metschl, Susanne Wu, Zhiyuan Koschinsky, Marlys L. Reilly, Muredach Pelisek, Jaroslav Kempf, Wolfgang Eckstein, Hans-Henning Soehnlein, Oliver Matic, Ljubica Hedin, Ulf Bäcklund, Alexandra Bergmark, Claes Paloschi, Valentina Maegdefessel, Lars |
author_sort | Fasolo, Francesca |
collection | PubMed |
description | Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The present study assessed the functional contribution of the lncRNA myocardial infarction-associated transcript (MIAT) to atherosclerosis and carotid artery disease. METHODS: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies. The lncRNA MIAT was identified as the most upregulated noncoding RNA transcript in carotid plaques compared with nonatherosclerotic control arteries, which was confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. RESULTS: Experimental knockdown of MIAT, using site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs) but also increased their apoptosis. MIAT mechanistically regulated SMC proliferation through the EGR1 (Early Growth Response 1)-ELK1 (ETS Transcription Factor ELK1)-ERK (Extracellular Signal-Regulated Kinase) pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat(–/–) and Miat(–/–)ApoE(–/–) mice, and Yucatan LDLR(–/–) mini-pigs, as well, confirmed the regulatory role of this lncRNA in SMC de- and transdifferentiation and advanced atherosclerotic lesion formation. CONCLUSIONS: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs, and the proinflammatory properties of macrophages, as well. |
format | Online Article Text |
id | pubmed-8570347 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-85703472021-11-12 Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization Fasolo, Francesca Jin, Hong Winski, Greg Chernogubova, Ekaterina Pauli, Jessica Winter, Hanna Li, Daniel Y. Glukha, Nadiya Bauer, Sabine Metschl, Susanne Wu, Zhiyuan Koschinsky, Marlys L. Reilly, Muredach Pelisek, Jaroslav Kempf, Wolfgang Eckstein, Hans-Henning Soehnlein, Oliver Matic, Ljubica Hedin, Ulf Bäcklund, Alexandra Bergmark, Claes Paloschi, Valentina Maegdefessel, Lars Circulation Original Research Articles Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The present study assessed the functional contribution of the lncRNA myocardial infarction-associated transcript (MIAT) to atherosclerosis and carotid artery disease. METHODS: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies. The lncRNA MIAT was identified as the most upregulated noncoding RNA transcript in carotid plaques compared with nonatherosclerotic control arteries, which was confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. RESULTS: Experimental knockdown of MIAT, using site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs) but also increased their apoptosis. MIAT mechanistically regulated SMC proliferation through the EGR1 (Early Growth Response 1)-ELK1 (ETS Transcription Factor ELK1)-ERK (Extracellular Signal-Regulated Kinase) pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat(–/–) and Miat(–/–)ApoE(–/–) mice, and Yucatan LDLR(–/–) mini-pigs, as well, confirmed the regulatory role of this lncRNA in SMC de- and transdifferentiation and advanced atherosclerotic lesion formation. CONCLUSIONS: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs, and the proinflammatory properties of macrophages, as well. Lippincott Williams & Wilkins 2021-10-14 2021-11-09 /pmc/articles/PMC8570347/ /pubmed/34647815 http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052023 Text en © 2021 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Research Articles Fasolo, Francesca Jin, Hong Winski, Greg Chernogubova, Ekaterina Pauli, Jessica Winter, Hanna Li, Daniel Y. Glukha, Nadiya Bauer, Sabine Metschl, Susanne Wu, Zhiyuan Koschinsky, Marlys L. Reilly, Muredach Pelisek, Jaroslav Kempf, Wolfgang Eckstein, Hans-Henning Soehnlein, Oliver Matic, Ljubica Hedin, Ulf Bäcklund, Alexandra Bergmark, Claes Paloschi, Valentina Maegdefessel, Lars Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization |
title | Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization |
title_full | Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization |
title_fullStr | Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization |
title_full_unstemmed | Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization |
title_short | Long Noncoding RNA MIAT Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization |
title_sort | long noncoding rna miat controls advanced atherosclerotic lesion formation and plaque destabilization |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570347/ https://www.ncbi.nlm.nih.gov/pubmed/34647815 http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052023 |
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