SR9009 improves heart function after pressure overload independent of cardiac REV-ERB
Hui Li1, Shiyang Song2, Chih-Liang Tien1
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
Insights
Genetic deletion of REV-ERB in heart cells worsens pressure overload damage. The drug SR9009 still protects the heart in these mice, indicating REV-ERB-independent mechanisms are involved in its cardioprotective effects.
Area of Science:
- Cardiovascular Biology
- Chronobiology
- Molecular Cardiology
Background:
- The core clock component REV-ERB plays a crucial role in maintaining heart function.
- REV-ERB agonist SR9009 has shown promise in ameliorating cardiac remodeling following pressure overload.
- The precise mechanism of SR9009's action, particularly its reliance on cardiac REV-ERB, remains unclear.
Purpose of the Study:
- To investigate the role of cardiac REV-ERB in response to pressure overload.
- To determine if the cardioprotective effects of SR9009 are mediated through cardiac REV-ERB.
- To elucidate the mechanisms underlying SR9009's protective effects on the heart.
Main Methods:
- Generation of REV-ERBα/β cardiac-specific double knockout (cDKO) mice.
- Induction of pressure overload using the transverse aortic constriction (TAC) model.
- Administration of SR9009 at different time points relative to REV-ERB expression cycles.
Main Results:
- REV-ERB cardiac deficiency exacerbated cardiac myopathy and adverse remodeling after TAC in cDKO mice compared to wild-type controls.
- SR9009 demonstrated significant cardioprotective effects against TAC-induced injury in cDKO mice, independent of cardiac REV-ERB.
- The timing of SR9009 administration did not alter its cardioprotective efficacy, further supporting REV-ERB-independent pathways.
Conclusions:
- Cardiac REV-ERB is critical for protecting the heart against pressure overload-induced damage.
- SR9009 exerts cardioprotection through mechanisms independent of direct REV-ERB signaling in cardiomyocytes.
- These findings reveal novel insights into the therapeutic potential of SR9009 for heart conditions.
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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