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Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells

Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs...

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Autores principales: Das, Sadhan, Senapati, Parijat, Chen, Zhuo, Reddy, Marpadga A., Ganguly, Rituparna, Lanting, Linda, Mandi, Varun, Bansal, Anita, Leung, Amy, Zhang, Selena, Jia, Ye, Wu, Xiwei, Schones, Dustin E., Natarajan, Rama
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684340/
https://www.ncbi.nlm.nih.gov/pubmed/29133788
http://dx.doi.org/10.1038/s41467-017-01629-7
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author Das, Sadhan
Senapati, Parijat
Chen, Zhuo
Reddy, Marpadga A.
Ganguly, Rituparna
Lanting, Linda
Mandi, Varun
Bansal, Anita
Leung, Amy
Zhang, Selena
Jia, Ye
Wu, Xiwei
Schones, Dustin E.
Natarajan, Rama
author_facet Das, Sadhan
Senapati, Parijat
Chen, Zhuo
Reddy, Marpadga A.
Ganguly, Rituparna
Lanting, Linda
Mandi, Varun
Bansal, Anita
Leung, Amy
Zhang, Selena
Jia, Ye
Wu, Xiwei
Schones, Dustin E.
Natarajan, Rama
author_sort Das, Sadhan
collection PubMed
description Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies.
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spelling pubmed-56843402017-11-17 Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells Das, Sadhan Senapati, Parijat Chen, Zhuo Reddy, Marpadga A. Ganguly, Rituparna Lanting, Linda Mandi, Varun Bansal, Anita Leung, Amy Zhang, Selena Jia, Ye Wu, Xiwei Schones, Dustin E. Natarajan, Rama Nat Commun Article Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies. Nature Publishing Group UK 2017-11-13 /pmc/articles/PMC5684340/ /pubmed/29133788 http://dx.doi.org/10.1038/s41467-017-01629-7 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Das, Sadhan
Senapati, Parijat
Chen, Zhuo
Reddy, Marpadga A.
Ganguly, Rituparna
Lanting, Linda
Mandi, Varun
Bansal, Anita
Leung, Amy
Zhang, Selena
Jia, Ye
Wu, Xiwei
Schones, Dustin E.
Natarajan, Rama
Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
title Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
title_full Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
title_fullStr Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
title_full_unstemmed Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
title_short Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
title_sort regulation of angiotensin ii actions by enhancers and super-enhancers in vascular smooth muscle cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684340/
https://www.ncbi.nlm.nih.gov/pubmed/29133788
http://dx.doi.org/10.1038/s41467-017-01629-7
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