Cardiac Circadian Clock and Dilated Cardiomyopathy

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Project Summary/Abstract Rev-erbα/β are druggable components of the molecular circadian clock. How cardiac Rev-erb regulates heart function has not been studied in vivo. We generated a cardiomyocyte-specific Rev-erbα/β double knockout (Rev- CKO) mouse model. Rev-CKO mice display progressive dilated cardiomyopathy that leads to heart failure and complete lethality. In adult Rev-CKO mice, inducible cardiomyocyte-specific re-expression of Rev-erbα that is in-phase, but not anti-phase, with its endogenous oscillation pattern rescued contractile defects and heart failure, demonstrating the importance of the Rev-erb oscillation per se in cardiac functions. RNA-seq, ChIP-seq, metabolomics, and metabolic tracer studies revealed profound alterations in mitochondrial oxidative metabolism in the Rev-CKO heart, particularly at night. We hypothesize that Rev-erb regulates heart function through temporal coordination of anticipatory expression of metabolic genes and the diurnal lipid availability to the myocardium. We will determine how cardiac Rev-erb regulates gene expression oscillation and how the oscillation affects cardiac functions; delineate the molecular mechanism underlying cardiac Rev-erb-mediated gene expression regulation; explore how cardiac Rev-erb regulates myocardial metabolism; and characterize Rev-erb agonist in treating dilated cardiomyopathy. Using a new mouse model, a novel phase-restricted re- expression technique, and integrative multi-omics approaches, we aim to provide new insights into how the circadian clock regulates gene expression and “housekeeping” functions such as energy metabolism in cardiomyocytes in the pathobiology of heart failure, which can potentially lay an intellectual groundwork for novel chronotherapy strategies of dilated cardiomyopathy.