Abstract Body (Do not enter title and authors here): Background: Circadian clock plays a vital role in heart physiology and diseases. The nuclear receptor REV-ERBα/β is a key component of the circadian clock. Previous study has shown cardiac deficiency of REV-ERBα/β leads to dilated cardiomyopathy, supporting its essential role in healthy heart homeostasis. However, a specific REV-ERBα/β agonist has not been available to directly demonstrate in vivo efficacy in treating heart failure.

Aim: This study aims to test the effect of a novel REV-ERBα/β agonist (P-1799) in a heart failure model induced by pressure overload (transverse aortic constriction, TAC).

Methods: Wild type (WT) C57BL/6J mice underwent sham or TAC surgery at the age of 9 weeks. After TAC, mice were given P-1799 (20 mg/kg/day) or Vehicle (the diluent of the same volume) via intraperitoneal (IP) injection once daily for 6 weeks. Four groups were included: 1799-TAC group (N=8), Vehicle-TAC group (N=8), 1799-Sham group (N=4) and Vehicle-Sham group (N=4). Echocardiography was performed before TAC and 1, 2, 4 and 6 weeks after TAC. Mice hearts were harvested 6 weeks after TAC for pathology. The apexes of the mouse hearts were processed for single nuclei isolation and libraries construction. Both pseudo bulk and cell type specific analysis were performed.

WT and REV-ERBα/β cardiac knockout mice (TKN1N2) underwent sham or TAC surgery as above. Four groups were included: 1799-TAC group (N=10), Vehicle-TAC group (N=8), 1799-Sham group (N=6) and Vehicle-Sham group (N=6). Echocardiogram and postmortem analysis were performed as above.

Results: Mice in the 1799-TAC group showed a significantly improved LV ejection fraction (Fig 1A), less hypertrophy (Fig 1B-D) and fibrosis (Fig 1E-F), when compared to mice in the Vehicle-TAC group 6 weeks after TAC. As expected, TKN1N2 mice did not show any cardiac protection from P-1799 treatment, demonstrating target specificity (Fig 1G). Pseudo bulk analysis from snRNAseq showed P-1799 abolished the TAC induced gene expression changes (Fig 1H). Further, TAC induced cell states shift in cardiomyocytes and fibroblasts were abolished by P-1700 treatment.


Conclusions: Novel Rev-erb α/β agonist P-1799 protects cardiac function and ameliorates hypertrophy and fibrosis by directly repress pathological gene expression changes in a murine pressure overload model. P-1799 and other Rev-erb α/β agonist hold the potential as future heart failure therapy.