Heart failure (HF) is associated with a 5-year mortality of 50% and the incidence is still rising. Identifying novel strategies to HF is of urgent clinical need. One missed opportunity is that HF is associated with a stereotypical gene expression program, however, the current therapy focuses on improving hemodynamics and neurohormonal milieu, the already committed gene program is not reversed. We have identified a circadian repressor REV-ERB?, which binds near pathological driver transcription factor MEF2s in the heart and prevents pathological gene program activation during HF. We demonstrated that pharmacological agonist of REV-ERB? ameliorates cardiac hypertrophy and HF during a variety of stresses both as prevention and as late disease stabilization. Cardiac deletion of REV-ERB? and b leads to exaggerated heart failure after pressure overload and spontaneously with aging. Further, we found REV-ERB? agonist has a similar effect in human induced pluripotent stem cells derived cardiomyocytes. We thus hypothesize that REV-ERB? inhibits cardiac pathological remodeling through transcriptional repression at the aberrantly activated MEF2 enhancers. Our long-term goal is to understand how REV-ERB? inhibits gene program in the cardiomyocytes and develop REV-ERB? enhancement as a novel therapeutic strategy for HF. In this proposal, we have two specific aims towards this goal: (1) define the role of REV-ERB in the cardiomyocytes at rest and under cardiac stress; (2) determine the molecular basis of REV-ERB? and MEF2c interaction during cardiac remodeling. Completion of this proposal will have significant impact in understanding gene regulation in the heart during pathological remodeling and potentially expand our therapeutic strategies for HF treatment.
Heart failure has a circadian rhythmicity and is associated with a stereotypical gene expression program. We have identified a circadian repressor that suppress the switch to the pathological gene program in the heart. Understanding how the circadian machinery controls gene expression programs in the heart may lead to novel intervention for heart failure.