Key result
REV-ERB α/β deletion in cardiac fibroblasts increased myofibroblast activation, while the agonist SR9009 suppressed activation independently of REV-ERB.
Why the study?
REV-ERB agonists have shown antifibrotic effects in the heart and other organs, but the function of REV-ERB in cardiac fibroblasts remained unstudied.
REV-ERB is essential for maintaining cardiac fibroblasts in a quiescent state, but the anti-fibrotic effects of the REV-ERB agonist SR9009 occur independently of REV-ERB, highlighting the need for more specific agonists.
Caution against using SR9009 as a selective REV-ERB agonist in fibrosis studies; leaves open the development of more specific compounds for cardiac applications.
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.
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Luo et al. (2022) studied Cardiac fibrosis. REV-ERB deletion and SR9009 vs. Control (Ad-GFP infected) fibroblasts and vehicle was evaluated on Fibroblast activation (measured by α-SMA expression and myofibroblast markers). REV-ERB α/β deletion in cardiac fibroblasts increased myofibroblast activation, while the agonist SR9009 suppressed activation independently of REV-ERB.
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