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Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction

Rationale: Long non-coding RNA (lncRNAs) has been identified as a pivotal novel regulators in cardiac development as well as cardiac pathogenesis. lncRNA H19 is known as a fetal gene but it is exclusively abundant in the heart and skeletal muscles in adulthood, and is evolutionarily conserved in hum...

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Autores principales: Choong, Oi Kuan, Chen, Chen-Yun, Zhang, Jianhua, Lin, Jen-Hao, Lin, Po-Ju, Ruan, Shu-Chian, Kamp, Timothy J., Hsieh, Patrick C.H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771230/
https://www.ncbi.nlm.nih.gov/pubmed/31588235
http://dx.doi.org/10.7150/thno.35218
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author Choong, Oi Kuan
Chen, Chen-Yun
Zhang, Jianhua
Lin, Jen-Hao
Lin, Po-Ju
Ruan, Shu-Chian
Kamp, Timothy J.
Hsieh, Patrick C.H.
author_facet Choong, Oi Kuan
Chen, Chen-Yun
Zhang, Jianhua
Lin, Jen-Hao
Lin, Po-Ju
Ruan, Shu-Chian
Kamp, Timothy J.
Hsieh, Patrick C.H.
author_sort Choong, Oi Kuan
collection PubMed
description Rationale: Long non-coding RNA (lncRNAs) has been identified as a pivotal novel regulators in cardiac development as well as cardiac pathogenesis. lncRNA H19 is known as a fetal gene but it is exclusively abundant in the heart and skeletal muscles in adulthood, and is evolutionarily conserved in humans and mice. It has been reported to possess a significant correlation with the risk of coronary artery diseases. However, the function of H19 is not well characterized in heart. Methods: Loss-of-function and gain-of-function mouse models with left anterior descending coronary artery-ligation surgery were utilized to evaluate the functionality of H19 in vivo. For mechanistic studies, hypoxia condition were exerted in in vitro models to mimic cardiac ischemic injury. Chromatin isolation by RNA immunoprecipitation (ChIRP) was performed to reveal the interacting protein of lncRNA H19. Results: lncRNA H19 was significantly upregulated in the infarct area post-surgery day 4 in mouse model. Ectopic expression of H19 in the mouse heart resulted in severe cardiac dilation and fibrosis. Several extracellular matrix (ECM) genes were significantly upregulated. While genetic ablation of H19 by CRISPR-Cas9 ameliorated post-MI cardiac remodeling with reduced expression in ECM genes. Through chromatin isolation by RNA purification (ChIRP), we identified Y-box-binding protein (YB)-1, a suppressor of Collagen 1A1, as an interacting protein of H19. Furthermore, H19 acted to antagonize YB-1 through direct interaction under hypoxia, which resulted in de-repression of Collagen 1A1 expression and cardiac fibrosis. Conclusions: Together these results demonstrate that lncRNA H19 and its interacting protein YB-1 are crucial for ECM regulation during cardiac remodeling.
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spelling pubmed-67712302019-10-06 Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction Choong, Oi Kuan Chen, Chen-Yun Zhang, Jianhua Lin, Jen-Hao Lin, Po-Ju Ruan, Shu-Chian Kamp, Timothy J. Hsieh, Patrick C.H. Theranostics Research Paper Rationale: Long non-coding RNA (lncRNAs) has been identified as a pivotal novel regulators in cardiac development as well as cardiac pathogenesis. lncRNA H19 is known as a fetal gene but it is exclusively abundant in the heart and skeletal muscles in adulthood, and is evolutionarily conserved in humans and mice. It has been reported to possess a significant correlation with the risk of coronary artery diseases. However, the function of H19 is not well characterized in heart. Methods: Loss-of-function and gain-of-function mouse models with left anterior descending coronary artery-ligation surgery were utilized to evaluate the functionality of H19 in vivo. For mechanistic studies, hypoxia condition were exerted in in vitro models to mimic cardiac ischemic injury. Chromatin isolation by RNA immunoprecipitation (ChIRP) was performed to reveal the interacting protein of lncRNA H19. Results: lncRNA H19 was significantly upregulated in the infarct area post-surgery day 4 in mouse model. Ectopic expression of H19 in the mouse heart resulted in severe cardiac dilation and fibrosis. Several extracellular matrix (ECM) genes were significantly upregulated. While genetic ablation of H19 by CRISPR-Cas9 ameliorated post-MI cardiac remodeling with reduced expression in ECM genes. Through chromatin isolation by RNA purification (ChIRP), we identified Y-box-binding protein (YB)-1, a suppressor of Collagen 1A1, as an interacting protein of H19. Furthermore, H19 acted to antagonize YB-1 through direct interaction under hypoxia, which resulted in de-repression of Collagen 1A1 expression and cardiac fibrosis. Conclusions: Together these results demonstrate that lncRNA H19 and its interacting protein YB-1 are crucial for ECM regulation during cardiac remodeling. Ivyspring International Publisher 2019-08-21 /pmc/articles/PMC6771230/ /pubmed/31588235 http://dx.doi.org/10.7150/thno.35218 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Choong, Oi Kuan
Chen, Chen-Yun
Zhang, Jianhua
Lin, Jen-Hao
Lin, Po-Ju
Ruan, Shu-Chian
Kamp, Timothy J.
Hsieh, Patrick C.H.
Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
title Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
title_full Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
title_fullStr Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
title_full_unstemmed Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
title_short Hypoxia-induced H19/YB-1 cascade modulates cardiac remodeling after infarction
title_sort hypoxia-induced h19/yb-1 cascade modulates cardiac remodeling after infarction
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771230/
https://www.ncbi.nlm.nih.gov/pubmed/31588235
http://dx.doi.org/10.7150/thno.35218
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