SR9009 Improves Heart Function After Pressure Overload Independent of Cardiac REV-ERB

Authors

Hui Li
Shiyang Song
Chih-Liang Tien
Lei Qi
Andrea Graves
Eleni Nasiotis
Thomas P Burris
Yuanbiao Zhao
Zheng Sun
Lilei Zhang

Publication Date

1-1-2022

Journal

Frontiers in Cardiovascular Medicine

DOI

10.3389/fcvm.2022.952114

PMID

35911512

PMCID

PMC9329699

PubMedCentral® Posted Date

7-14-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

circadian clock, REV-ERB, SR9009, TAC, heart disease

Abstract

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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