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

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.

REV-ERB is essential in cardiac fibroblasts homeostasis

“…Similar results were seen in both CFs and MEFs. Our results corroborated with previous reports and showed that SR9009 likely has off-target effects that contribute to its cardiac protective and anti-fibrotic functions ( Dierickx et al, 2019 ; Li et al, 2022 ). A more detailed study to identify the possible mechanisms and targets of SR9009 is beyond the scope of the current study.…”

“…Another REV-ERB agonist GSK4112 inhibits myofibroblasts activation in idiopathic pulmonary fibrosis (IPF) fibroblasts ( Cunningham et al, 2020 ). However, SR9009 has REV-ERB–independent effects in the mouse hepatocytes, embryonic stem cells and cardiomyocytes ( Li et al, 2022 ) ( Dierickx et al, 2019 ). Therefore, it is unclear whether REV-ERB has a cell-autonomous function in fibroblasts and whether the effect of SR9009 in fibroblasts is dependent on REV-ERB.…”

Circadian Clock in Muscle Disease Etiology and Therapeutic Potential for Duchenne Muscular Dystrophy

“…Accumulating research has firmly established that the circadian clock could be a novel therapeutic target for muscular dystrophy [27,54,56,58,153]. The molecular mechanisms underlying clock modulation of muscle mass, function, growth, and repair provide the mechanistic basis for exploring pharmacological interventions of clock activity to ameliorate dystrophic disease.…”