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

昼夜节律紊乱、心脏 GH/IGF-1 信号传导与心力衰竭之间的关系

• 批准号: 9898294
• 负责人: Stuart J Frank
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898294
• 关键词: ARNTL gene; Accounting; Address; Affect; Age; Age of Onset; Anterior Pituitary Hormones; Attenuated; Behavior; Behavior Control; Biological; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiomyopathies; Cardiovascular Diseases; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Complex; Data; Diet; Dilated Cardiomyopathy; Eating Behavior; Endocrine system; Environment; Exhibits; Fasting; Fostering; Functional disorder; Future; Gene Expression; Genetic; Genetic Polymorphism; Health; Health Expenditures; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Homeostasis; Hormonal; Hormone secretion; Hormones; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Individual; Insulin-Like Growth Factor I; Laboratories; Lead; Life Style; Light; Link; Longevity; Maintenance; Mediating; Modernization; Molecular; Mus; Myocardial dysfunction; Nature; Pathologic; Pathology; Phenotype; Physiology; Pituitary Hormones; Play; Predisposition; Prevention strategy; Public Health; Research; Role; Signal Transduction; Sleep; Sleep disturbances; Somatotrophin increased; Somatotropin; Stimulus; Stress; Testing; Therapeutic; Time; Tissues; United States; Veterans; Work; cardiogenesis; cardiometabolism; circadian; circadian pacemaker; feeding; gene environment interaction; heart function; hormone sensitivity; mortality; mouse model; novel; overexpression; response; restoration; shift work; sound; transcription factor; treatment strategy

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.

心血管疾病（CVD）是美国在CVD中死亡的主要原因，心力衰竭（HF）是一种sig- 重大的公共卫生负担不仅会给人类的痛苦做出贡献，还会增加医疗保健支出 - 它。 CVD出现在复杂的基因环境相互作用的环境中。内部的基本遗传学 分裂影响环境和激素刺激和压力如何影响心脏功能，并导致路径 Ology。心肌细胞昼夜节律是一种基因编程的固有细胞自主分子 允许心脏预测环境刺激和压力并随后促进的机制 维持心脏功能必不可少的反应。小鼠昼夜节律机制的破坏和 人类（例如，通过遗传多态性或环境改变，例如转移工作，睡眠障碍， 或饮食行为调节）对心脏代谢健康产生负面影响。此外，种系缺失 BMAL1是时钟机制的核心转录因子成分，它产生了年龄发作的心肌 - 病情和寿命降低。最近，我们发现BMAL1专门从心肌细胞中删除 （CBK小鼠）概括了这种病理表型，暴露了时钟的重要作用 心。但是，心肌细胞昼夜节律破坏导致心肌病的机制是 未知。多个内分泌系统成分是昼夜节律。有证据表明细胞自主cir- Cadian时钟不仅可以驱动激素的时间分泌，还可以调节日期依赖性目标 组织对这些激素的敏感性。这样，昼夜节律钟表稳态增加了一层。不仅这样做 对刺激的水平和敏感性起着重要的作用，但也是时机。循环水平 垂体激素，生长激素（GH），在人类中表现出显着的昼夜节律。相反，没有什么是 关于GH灵敏度的节奏已知。慢性GH升高产生心脏肿大和HF。 GH施加了许多 它通过诱导胰岛素样生长因子1（IGF-1）来生物学作用；心肌细胞特异性的小鼠模型 IGF-1过表达导致肥厚性心肌病。我们最近的初步数据表明了一天的时间 - 心脏中GH敏感性的依赖性振荡取决于心肌细胞昼夜节律。更多的- 结束时，CBK心脏具有更高的GH灵敏度，心脏IGF-1基因表达升高，心肌细胞 肥大和HF。总之，这些观察结果使我们假设心肌细胞大约 Dian Clock调节了GH的灵敏度，这种机制的破坏赋予了本地IGF-1介导 心脏肥大和HF通过增强的GH灵敏度。因此，我们将测试以下假设： 目标1。心肌细胞昼夜节律的GH灵敏度调节对于维持 心脏功能。我们将确定是否：1a。心肌细胞昼夜节律调节了 以日常依赖的方式（生理）到GH的心脏； 1B。心肌细胞的遗传破坏 昼夜节律时钟失衡GH/IGF-1信号轴，从而导致心肌病（病理）。 目标2。昼夜行为/环境参数的破坏（例如，禁食/喂食和光/黑暗 循环）增强心脏GH/IGF-1信号传导，从而倾向于收缩功能障碍。我们将 确定是否：2a。操纵昼夜节律行为（例如禁食/喂养周期）或环境（例如， 光/黑暗循环）心脏中的GH灵敏度和GH/IGF-1信号传导； 2b。恢复GH/IGF-1信号传导 在心脏中，环境/行为操纵后，会减轻收缩功能障碍的敏感性。 我们的研究将确定连接心肌细胞昼夜节律时钟功能障碍以增强的机制 心脏GH/IGF-1信号传导。由于与年龄相关的CBK心肌病与GH中相似 过度，我们的研究可能会促进一个新颖的概念，即GH过度和增强GH敏感性 普通昼夜节律诱导的Derlie心脏功能障碍（例如饮食，暴露，睡眠）， 并为针对HF中GH/IGF-1信号轴的未来治疗策略提供声音原理。