Relationship between circadian disruption, cardiac GH/IGF-1 signaling, and heart failure

心血管疾病（CVD）是美国死亡的主要原因。在CVD中，心力衰竭（HF）是一个标志性疾病。 巨大的公共卫生负担不仅造成人类痛苦，而且增加了医疗保健费用， itures。心血管疾病是在复杂的基因-环境相互作用的背景下出现的; 个别影响环境和激素刺激和压力如何影响心脏功能和导致路径- 学。心肌细胞生物钟是一种遗传程序化的内在细胞自主分子 允许心脏预测环境刺激和压力并随后促进 对维持心脏功能至关重要的反应。破坏小鼠的生物钟机制， 人类（例如，通过遗传多态性或环境改变，如轮班工作，睡眠障碍， 或饮食行为调节）负面地影响心脏代谢健康。此外， BMAL 1是时钟机制的核心转录因子成分，产生年龄发作扩张的心肌细胞， 疾病和寿命缩短。我们最近发现，心肌细胞中BMAL 1的缺失， (CBK小鼠）重现了这种病理表型，揭示了生物钟在细胞周期中的重要作用。 心然而，心肌细胞生物钟紊乱导致心肌病的机制是 未知多种内分泌系统成分是昼夜节律的。有证据表明细胞自主循环- 昼夜节律钟不仅驱动激素的时间分泌，而且调节时间依赖性靶点， 组织对这些激素的敏感性。这样一来，生物钟就为体内平衡增加了一层新的内容;不仅 刺激的水平和对刺激的敏感性起着重要的作用，但时机也是如此。的循环水平 垂体激素，生长激素（GH），在人体内表现出明显昼夜节律。相比之下， 知道生长激素敏感性的节律。慢性GH升高可导致心脏肥大和HF。GH发挥了许多 通过诱导胰岛素样生长因子-1（IGF-1）的生物学作用;心肌细胞特异性 IGF-1过表达导致肥厚型心肌病。我们最近的初步数据显示- 心脏中GH敏感性的依赖性振荡，这取决于心肌细胞生物钟。更多- 此外，CBK心脏表现出更高的GH敏感性，心脏IGF-1基因表达升高，心肌细胞 肥大和HF。总之，这些观察使我们假设心肌细胞大约- 生物钟调节生长激素敏感性，这种机制破坏会导致局部IGF-1介导的 通过增强GH敏感性导致心脏肥大和HF。因此，我们将检验以下假设： 目标1.生长激素敏感性的心肌细胞生物钟调节对于维持生长激素敏感性至关重要。 心脏功能我们将确定是否：1A。心肌细胞的生物钟调节 心脏以一天中的时间依赖性方式（生理学）对GH的依赖; 1B.心肌细胞的遗传破坏 生物钟失衡GH/IGF-1信号轴，从而诱发心肌病（病理学）。 目标2.昼夜节律行为/环境参数的破坏（例如，禁食/进食和光照/黑暗 周期）增强心脏GH/IGF-1信号传导，从而诱发收缩功能障碍。我们将 确定是否：2A.昼夜节律行为的操纵（例如，禁食/喂养周期）或环境（例如， 光/暗周期）影响心脏中的GH敏感性和GH/IGF-1信号传导; 2B.恢复GH/IGF-1信号传导 在环境/行为操纵后的心脏中，降低了对收缩功能障碍的易感性。 我们的研究将确定心肌细胞生物钟功能障碍与增强 心脏GH/IGF-1信号传导。由于年龄相关性CBK心肌病与GH中所见相似， 过量，我们的研究可能会促进新的概念，即GH过量和增强GH敏感性， 由常见的昼夜节律扰动（例如，饮食、光照、睡眠）， 并为将来针对HF中GH/IGF-1信号传导轴的治疗策略提供了合理的理论基础。

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.