Cardiovascular disease (CVD) is the leading cause of death in the United States with 25% of Americans suffering from one or more forms of CVD. Although procedural interventions have markedly increased survival following acute adverse cardiac events, heart failure (HF) incidence has more than doubled over the past 30 years. A plethora of putative mechanisms have been proposed in the pathogenesis of heart failure, ranging from extra-cardiac (e.g. volume and pressure overload, atherosclerosis, and inflammation) to intra-cardiac (e.g. extracellular matrix, signaling, enhanced protein synthesis, and metabolism). Despite this wealth of knowledge, significant barriers still exist in understanding the etiology of HF and translating this information to patient care. Hypertrophic growth is considered a foundational event in adverse cardiac remodeling in HF patients. Prior studies indicate that both sensitivity of the heart to pro-hypertrophic stimuli, and the processes critical for hypertrophic growth (e.g., protein synthesis) are exacerbated at the beginning of the sleep period, and that this time-of-day-dependence is mediated by a molecular timekeeping mechanism in cardiomyocytes. Namely the cardiomyocyte circadian clock (CCC). Interestingly, cardiomyocyte-specific BMAL1 knockout (CBK; BMAL1 is a critical clock component) temporally suspends the CCC at the beginning of the sleep phase, such that cardiac protein synthesis is chronically high throughout the day, leading to cardiomyocyte hypertrophy, adverse cardiac remodeling, and ultimately dilated cardiomyopathy. A key regulator of protein synthesis is mammalian target of rapamycin (mTOR), and we have recently reported that mTOR is chronically activated in CBK hearts, through an as yet undefined mechanism. Recent unbiased small RNA sequencing of wild-type (WT) and CBK hearts has revealed that miR-582 exhibits a 2-fold oscillation in WT hearts which is abrogated by the loss of BMAL1; miR-582 is chronically elevated in CBK hearts. A predicted target of miR-582 is Deptor (DEPDC6), a negative regulator of mTOR activity. Interestingly, we find that Deptor has a 2-fold oscillation in WT hearts, with lowest levels at the beginning of the sleep phase,and is chronically low in CBK hearts. Collectively, these observations have led to the hypothesis that the CCC facilitates cardiac growth/repair during the sleep period through the miR-582/Deptor/mTOR axis, and that disruption of the CCC chronically perturbs this signaling axis, resulting in cardiomyocyte hypertrophy and adverse cardiac remodeling.
Cardiovascular disease (CVD) is the leading cause of death in the United States with 25% of Americans suffering from one or more forms of CVD. Prior studies indicate that both sensitivity of the heart to pro-hypertrophic stimuli, and the processes critical for hypertrophic growth (e.g., protein synthesis) are exacerbated at the beginning of the sleep period, and that this time-of-day- dependence is mediated by a molecular timekeeping mechanism in cardiomyocytes. Collectively, these observations have led to the hypothesis that the CCC facilitates cardiac growth/repair during the sleep period through the miR-582/Deptor/mTOR axis, and that disruption of the CCC chronically perturbs this signaling axis, resulting in cardiomyocyte hypertrophy and adverse cardiac remodeling.
