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MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4
Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocy...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581305/ https://www.ncbi.nlm.nih.gov/pubmed/34643044 http://dx.doi.org/10.1111/jcmm.16985 |
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author | Ye, Qing Liu, Quan Ma, Xiaolong Bai, Shuyun Chen, Pengfei Zhao, Yichen Bai, Chen Liu, Yang Liu, Kemin Xin, Meng Zeng, Caiwu Zhao, Cheng Yao, Yan Ma, Yue Wang, Jiangang |
author_facet | Ye, Qing Liu, Quan Ma, Xiaolong Bai, Shuyun Chen, Pengfei Zhao, Yichen Bai, Chen Liu, Yang Liu, Kemin Xin, Meng Zeng, Caiwu Zhao, Cheng Yao, Yan Ma, Yue Wang, Jiangang |
author_sort | Ye, Qing |
collection | PubMed |
description | Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR‐146b‐5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR‐146b‐5p transfection in human induced pluripotent stem cell‐derived atrial cardiomyocytes (hiPSC‐aCMs)‐fibroblast co‐culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR‐146b‐5p downregulation on atrial fibrosis. The expression level of miR‐146b‐5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR‐146b‐5p transfection in hiPSC‐aCMs‐fibroblast co‐culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR‐146b‐5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR‐146b‐5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR‐146b‐5p overexpressed co‐culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR‐146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR‐146b‐5p might become an effective therapeutic approach for preventing atrial fibrosis. |
format | Online Article Text |
id | pubmed-8581305 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85813052021-11-17 MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 Ye, Qing Liu, Quan Ma, Xiaolong Bai, Shuyun Chen, Pengfei Zhao, Yichen Bai, Chen Liu, Yang Liu, Kemin Xin, Meng Zeng, Caiwu Zhao, Cheng Yao, Yan Ma, Yue Wang, Jiangang J Cell Mol Med Original Articles Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR‐146b‐5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR‐146b‐5p transfection in human induced pluripotent stem cell‐derived atrial cardiomyocytes (hiPSC‐aCMs)‐fibroblast co‐culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR‐146b‐5p downregulation on atrial fibrosis. The expression level of miR‐146b‐5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR‐146b‐5p transfection in hiPSC‐aCMs‐fibroblast co‐culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR‐146b‐5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR‐146b‐5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR‐146b‐5p overexpressed co‐culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR‐146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR‐146b‐5p might become an effective therapeutic approach for preventing atrial fibrosis. John Wiley and Sons Inc. 2021-10-13 2021-11 /pmc/articles/PMC8581305/ /pubmed/34643044 http://dx.doi.org/10.1111/jcmm.16985 Text en © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Ye, Qing Liu, Quan Ma, Xiaolong Bai, Shuyun Chen, Pengfei Zhao, Yichen Bai, Chen Liu, Yang Liu, Kemin Xin, Meng Zeng, Caiwu Zhao, Cheng Yao, Yan Ma, Yue Wang, Jiangang MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 |
title | MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 |
title_full | MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 |
title_fullStr | MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 |
title_full_unstemmed | MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 |
title_short | MicroRNA‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4 |
title_sort | microrna‐146b‐5p promotes atrial fibrosis in atrial fibrillation by repressing timp4 |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581305/ https://www.ncbi.nlm.nih.gov/pubmed/34643044 http://dx.doi.org/10.1111/jcmm.16985 |
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