REV-ERB is Essential in Cardiac Fibroblasts Homeostasis

Authors

Xiaokang Luo
Shiyang Song
Lei Qi
Chih-Liang Tien
Hui Li
Weiyi Xu
Theodore Lemuel Mathuram
Thomas Burris
Yuanbiao Zhao
Zheng Sun
Lilei Zhang

Publication Date

1-1-2022

Journal

Frontiers in Pharmacology

DOI

10.3389/fphar.2022.899628

PMID

36386186

PMCID

PMC9662302

Published Open-Access

no

Keywords

REV-ERB, fibroblast activation, SR9009, cardiac fibroblasts, TGFβ

Abstract

REV-ERB agonists have shown antifibrotic effects in the heart and other organs. The function of REV-ERB in the cardiac fibroblasts remains unstudied. Here, we characterize the functional difference of REV-ERB in mouse embryonic fibroblasts and cardiac fibroblasts using genetic deletion of REV-ERBα and ß in vitro. We show that REV-ERB α/β double deleted cardiac fibroblasts have reduced viability and proliferation, but increased migration and myofibroblasts activation. Thus, REV-ERB α/β has essential cell-autonomous role in cardiac fibroblasts in maintaining them in a healthy, quiescent state. We also show that existing REV-ERB agonist SR9009 strongly suppresses cardiac fibroblasts activation but in a REV-ERB-independent manner highlighting the need to develop novel REV-ERB agonists for treating cardiac fibrosis.