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SR9009 improves heart function after pressure overload independent of cardiac REV-ERB

The core clock component REV-ERB is essential for heart function. Previous studies show that REV-ERB agonist SR9009 ameliorates heart remodeling in the pressure overload model with transverse aortic constriction (TAC). However, it is unknown whether SR9009 indeed works through cardiac REV-ERB, given...

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Autores principales: Li, Hui, Song, Shiyang, Tien, Chih-liang, Qi, Lei, Graves, Andrea, Nasiotis, Eleni, Burris, Thomas P., Zhao, Yuanbiao, Sun, Zheng, Zhang, Lilei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329699/
https://www.ncbi.nlm.nih.gov/pubmed/35911512
http://dx.doi.org/10.3389/fcvm.2022.952114
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author Li, Hui
Song, Shiyang
Tien, Chih-liang
Qi, Lei
Graves, Andrea
Nasiotis, Eleni
Burris, Thomas P.
Zhao, Yuanbiao
Sun, Zheng
Zhang, Lilei
author_facet Li, Hui
Song, Shiyang
Tien, Chih-liang
Qi, Lei
Graves, Andrea
Nasiotis, Eleni
Burris, Thomas P.
Zhao, Yuanbiao
Sun, Zheng
Zhang, Lilei
author_sort Li, Hui
collection PubMed
description The core clock component REV-ERB is essential for heart function. Previous studies show that REV-ERB agonist SR9009 ameliorates heart remodeling in the pressure overload model with transverse aortic constriction (TAC). However, it is unknown whether SR9009 indeed works through cardiac REV-ERB, given that SR9009 might target other proteins and that REV-ERB in non-cardiac tissues might regulate cardiac functions indirectly. To address this question, we generated the REV-ERBα/β cardiac-specific double knockout mice (cDKO). We found that REV-ERB cardiac deficiency leads to profound dilated cardiac myopathy after TAC compared to wild-type (WT) control mice, confirming the critical role of REV-ERB in protecting against pressure overload. Interestingly, the cardioprotective effect of SR9009 against TAC retains in cDKO mice. In addition, SR9009 administered at the time points corresponding to the peak or trough of REV-ERB expression showed similar cardioprotective effects, suggesting the REV-ERB-independent mechanisms in SR9009-mediated post-TAC cardioprotection. These findings highlight that genetic deletion of REV-ERB in cardiomyocytes accelerates adverse cardiac remodeling in response to pressure overload and demonstrated the REV-ERB-independent cardioprotective effect of SR9009 upon pressure overload.
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spelling pubmed-93296992022-07-29 SR9009 improves heart function after pressure overload independent of cardiac REV-ERB Li, Hui Song, Shiyang Tien, Chih-liang Qi, Lei Graves, Andrea Nasiotis, Eleni Burris, Thomas P. Zhao, Yuanbiao Sun, Zheng Zhang, Lilei Front Cardiovasc Med Cardiovascular Medicine The core clock component REV-ERB is essential for heart function. Previous studies show that REV-ERB agonist SR9009 ameliorates heart remodeling in the pressure overload model with transverse aortic constriction (TAC). However, it is unknown whether SR9009 indeed works through cardiac REV-ERB, given that SR9009 might target other proteins and that REV-ERB in non-cardiac tissues might regulate cardiac functions indirectly. To address this question, we generated the REV-ERBα/β cardiac-specific double knockout mice (cDKO). We found that REV-ERB cardiac deficiency leads to profound dilated cardiac myopathy after TAC compared to wild-type (WT) control mice, confirming the critical role of REV-ERB in protecting against pressure overload. Interestingly, the cardioprotective effect of SR9009 against TAC retains in cDKO mice. In addition, SR9009 administered at the time points corresponding to the peak or trough of REV-ERB expression showed similar cardioprotective effects, suggesting the REV-ERB-independent mechanisms in SR9009-mediated post-TAC cardioprotection. These findings highlight that genetic deletion of REV-ERB in cardiomyocytes accelerates adverse cardiac remodeling in response to pressure overload and demonstrated the REV-ERB-independent cardioprotective effect of SR9009 upon pressure overload. Frontiers Media S.A. 2022-07-14 /pmc/articles/PMC9329699/ /pubmed/35911512 http://dx.doi.org/10.3389/fcvm.2022.952114 Text en Copyright © 2022 Li, Song, Tien, Qi, Graves, Nasiotis, Burris, Zhao, Sun and Zhang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Li, Hui
Song, Shiyang
Tien, Chih-liang
Qi, Lei
Graves, Andrea
Nasiotis, Eleni
Burris, Thomas P.
Zhao, Yuanbiao
Sun, Zheng
Zhang, Lilei
SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
title SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
title_full SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
title_fullStr SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
title_full_unstemmed SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
title_short SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
title_sort sr9009 improves heart function after pressure overload independent of cardiac rev-erb
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329699/
https://www.ncbi.nlm.nih.gov/pubmed/35911512
http://dx.doi.org/10.3389/fcvm.2022.952114
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