Cardiovascular disease (CVD) is a major cause of mortality in the U.S. Among CVDs, heart failure (HF) is a sig- nificant public health burden contributing not only to human suffering, but also to increasing healthcare expend- itures. CVDs arise in the setting of complex gene-environment interactions; the underlying genetics within an in- dividual influences how environmental and hormonal stimuli and stresses affect cardiac function and cause path- ology. The cardiomyocyte circadian clock is a genetically-programmed intrinsic cell-autonomous molecular mechanism that allows the heart to anticipate environmental stimuli and stresses and subsequently facilitates responses essential for maintaining cardiac function. Disruption of the circadian clock mechanism in mice and humans (e.g., through genetic polymorphisms or environmental alterations such as shift work, sleep disturbance, or eating behavior modulation) negatively impact cardiometabolic health. Furthermore, germline deletion of BMAL1, a core transcription factor component of the clock mechanism, yields an age onset dilated cardiomyo- pathy and reduced lifespan. We recently found that BMAL1 deletion specifically from cardiomyocytes (CBK mouse) recapitulates this pathologic phenotype, exposing an essential role for the clock in the heart. However, the mechanism by which cardiomyocyte circadian clock disruption leads to cardiomyopathy is unknown. Multiple endocrine system components are circadian. Evidence is emerging that cell autonomous cir- cadian clocks not only drive the temporal secretion of hormones, but also modulate time-of-day-dependent target tissue sensitivity to these hormones. In doing so, circadian clocks add a new layer to homeostasis; not only do the level of, and the sensitivity to, a stimulus play an important role, but also the timing. Circulating levels of the pituitary hormone, growth hormone (GH), exhibit notable circadian rhythm in humans. In contrast, nothing is known about rhythms in GH sensitivity. Chronic GH elevation yields cardiomegaly and HF. GH exerts many of its biological actions by inducing insulin-like growth factor-1 (IGF-1); a mouse model of cardiomyocyte-specific IGF-1 overexpression results in hypertrophic cardiomyopathy. Our recent preliminary data suggest time-of-day- dependent oscillation of GH sensitivity in the heart, which depends on the cardiomyocyte circadian clock. More- over, CBK hearts exhibit greater GH sensitivity, with elevated cardiac IGF-1 gene expression, cardiomyocyte hypertrophy, and HF. Together, these observations lead us to hypothesize that the cardiomyocyte circa- dian clock modulates GH sensitivity, and that disruption of this mechanism confers local IGF-1-mediated cardiac hypertrophy and HF via augmented GH sensitivity. Accordingly, we will test the hypotheses that:
Aim 1. Cardiomyocyte circadian clock modulation of GH sensitivity is essential for maintenance of cardiac function. We will determine whether: 1A. The cardiomyocyte circadian clock modulates sensitivity of the heart to GH in a time-of-day-dependent manner (physiology); 1B. Genetic disruption of the cardiomyocyte circadian clock imbalances the GH/IGF-1 signaling axis, thereby precipitating cardiomyopathy (pathology).
Aim 2. Disruption of circadian behaviors/environmental parameters (e.g., fasting/feeding and light/dark cycles) augments cardiac GH/IGF-1 signaling, thereby predisposing to contractile dysfunction. We will determine whether: 2A. Manipulation of circadian behavior (e.g., fasting/feeding cycles) or environment (e.g., light/dark cycle) impact GH sensitivity and GH/IGF-1 signaling in the heart; 2B. Restoration of GH/IGF-1 signaling in the heart following environmental/behavioral manipulations attenuates susceptibility to contractile dysfunction. Our studies will identify mechanisms linking cardiomyocyte circadian clock dysfunction to augmented cardiac GH/IGF-1 signaling. As age-associated CBK cardiomyopathy has similarity with that seen in GH excess, our studies may foster the novel concept that both GH excess and enhanced GH sensitivity un- derlie cardiac dysfunction induced by common circadian perturbations (e.g., diet, light exposure, sleep), and provide sound rationale for future therapeutic strategies targeting the GH/IGF-1 signaling axis in HF.

Public Health Relevance

Heart disease, including heart failure, is a major national health problem, accounting for substantial human suffering and large health care expenditures. Veterans suffer disproportionately from heart disease. Reasons for these findings are not yet clear. One potential factor underlying heart disease is the disruption of the normal time-of-day (circadian) hormonal rhythms that increasingly characterizes our modern lifestyle (shift-work, sleep disturbance, altered diet). The proposed novel research explores the relationship between circadian disturbance in the heart, altered local heart hormone actions, and the development of heart failure. Although this work will be performed in mice, it has large implications for human, especially Veteran, health, particularly because it is likely that new heart failure prevention and treatment strategies will emerge that target the abnormal growth hormone (GH) action in the heart that we observe and will decipher.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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Birmingham VA Medical Center
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Liu, Ying; Jiang, Jing; Lepik, Bradford et al. (2017) Subdomain 2, Not the Transmembrane Domain, Determines the Dimerization Partner of Growth Hormone Receptor and Prolactin Receptor. Endocrinology 158:3235-3248
Sawada, Takahiro; Arai, Daiki; Jing, Xuefeng et al. (2017) Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B. PLoS One 12:e0180785
McGinnis, Graham R; Tang, Yawen; Brewer, Rachel A et al. (2017) Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart. J Mol Cell Cardiol 110:80-95
Hjortebjerg, Rikke; Berryman, Darlene E; Comisford, Ross et al. (2017) Insulin, IGF-1, and GH Receptors Are Altered in an Adipose Tissue Depot-Specific Manner in Male Mice With Modified GH Action. Endocrinology 158:1406-1418