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: 9349692
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349692
• 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 Rhythms; Complex; Darkness; Data; Diet; Dilated Cardiomyopathy; Eating Behavior; Endocrine system; Environment; Exhibits; Expenditure; Fasting; Fostering; Functional disorder; Future; Gene Expression; Genetic; Genetic Polymorphism; Health; Health Expenditures; Healthcare; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Homeostasis; Hormonal; 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; circadian pacemaker; feeding; gene environment interaction; 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）是美国人死亡的主要原因。在 CVD 中，心力衰竭（HF）是一个重要的疾病。 巨大的公共卫生负担不仅造成人类痛苦，而且增加医疗保健支出 物品。 CVD 是在复杂的基因与环境相互作用的背景下产生的；体内的潜在遗传学 个体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 学。心肌细胞生物钟是一种基因编程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的机制 维持心脏功能所必需的反应。小鼠生物钟机制的破坏 人类（例如，通过基因多态性或环境改变，如轮班工作、睡眠障碍、 或饮食行为调节）会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，可产生年龄开始扩张的心肌 可怜并缩短寿命。我们最近发现 BMAL1 特异地从心肌细胞中缺失 （CBK 小鼠）重现了这种病理表型，揭示了时钟在 心。然而，心肌细胞生物钟破坏导致心肌病的机制是 未知。多个内分泌系统组成部分具有昼夜节律。越来越多的证据表明细胞自主循环 生理时钟不仅驱动激素的暂时分泌，还调节一天中时间依赖性的目标 组织对这些激素的敏感性。在此过程中，生物钟为体内平衡添加了新的一层。不仅做 刺激的强度和敏感性起着重要作用，而且刺激的时机也很重要。的循环水平 垂体激素、生长激素（GH）在人类中表现出显着的昼夜节律。相比之下，没有什么是 了解 GH 敏感性节律。慢性 GH 升高会导致心脏肥大和心力衰竭。 GH发挥许多作用 通过诱导胰岛素样生长因子-1 (IGF-1) 发挥其生物作用；心肌细胞特异性小鼠模型 IGF-1 过度表达会导致肥厚型心肌病。我们最近的初步数据表明一天中的时间- 心脏中 GH 敏感性的依赖性振荡，取决于心肌细胞生物钟。更多的- 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 肥大和心力衰竭。总之，这些观察结果使我们推测心肌细胞循环 dian 时钟调节 GH 敏感性，并且该机制的破坏赋予局部 IGF-1 介导的 通过增强 GH 敏感性导致心脏肥大和心力衰竭。因此，我们将检验以下假设： 目标 1. 心肌细胞昼夜节律时钟对 GH 敏感性的调节对于维持 心脏功能。我们将确定是否：1A。心肌细胞生物钟调节敏感性 心脏以一天中不同时间的方式对 GH 进行调节（生理学）； 1B.心肌细胞的遗传破坏 生物钟使 GH/IGF-1 信号轴失衡，从而诱发心肌病（病理学）。 目标 2. 扰乱昼夜节律行为/环境参数（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 判断是否：2A。操纵昼夜节律行为（例如，禁食/进食周期）或环境（例如， 光/暗循环）影响心脏中的 GH 敏感性和 GH/IGF-1 信号传导； 2B。 GH/IGF-1 信号传导的恢复 环境/行为操纵后的心脏会减弱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的联系机制 心脏 GH/IGF-1 信号传导。由于年龄相关的 CBK 心肌病与 GH 中所见的相似 过量，我们的研究可能会提出一个新概念，即 GH 过量和 GH 敏感性增强都不会 由常见昼夜节律扰动（例如饮食、光照、睡眠）引起的心脏功能障碍， 并为未来针对 HF 的 GH/IGF-1 信号轴的治疗策略提供合理的理由。