Key result
SR9009 administration normalized ejection fraction to 53.8% compared to 20.9% with vehicle in REV-ERB knockout mice 4 weeks after transverse aortic constriction, demonstrating REV-ERB-independent cardioprotection.
Why the study?
It was unknown whether the REV-ERB agonist SR9009 ameliorates heart remodeling after transverse aortic constriction through cardiac REV-ERB or via off-target or non-cardiac tissue mechanisms.
The cardioprotective effects of the REV-ERB agonist SR9009 in pressure overload-induced heart failure are mediated through REV-ERB-independent mechanisms.
SR9009's REV-ERB-independent effects in animal HF models warrant no clinical consideration; leaves open alternative targets for future mechanistic studies.
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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Li et al. (2022) studied Pressure overload-induced heart failure. SR9009 vs. Vehicle was evaluated on Ejection fraction at 4 weeks post-TAC (p=<0.0001). SR9009 administration normalized ejection fraction to 53.8% compared to 20.9% with vehicle in REV-ERB knockout mice 4 weeks after transverse aortic constriction, demonstrating REV-ERB-independent cardioprotection.
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