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。在心血管疾病中，心力衰竭(HF)是一种重要的心血管疾病。 巨大的公共卫生负担不仅加剧了人类的痛苦，而且增加了医疗支出- 这些都是物件。心血管疾病发生在复杂的基因-环境相互作用的背景下； 个体影响环境和荷尔蒙刺激和压力如何影响心脏功能和致病途径- 学。心肌细胞生物钟是一种遗传编程的内在细胞自主分子 一种机制，允许心脏预见环境刺激和压力，并随后促进 对维持心脏功能至关重要的反应。扰乱小鼠的生物钟机制和 人类(例如，通过基因多态或环境变化，例如轮班工作，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，生殖系的缺失 BMal1是时钟机制的核心转录因子成分，产生一种年龄起病的扩张型心肌- 悲痛和缩短的寿命。我们最近发现，BMAL1特异性地从心肌细胞中缺失 (CBK小鼠)概括了这种病理表型，揭示了时钟在 心。然而，心肌细胞昼夜节律紊乱导致心肌病的机制是 未知。多种内分泌系统成分都是昼夜节律的。有证据表明，细胞自主循环-- 卡迪亚时钟不仅驱动激素的暂时分泌，而且还调节一天中的时间依赖的目标 组织对这些荷尔蒙的敏感性。在这样做的过程中，生物钟为动态平衡增加了新的一层；不仅 刺激的水平和敏感度起着重要作用，但时机也是如此。空气中的循环水平 垂体激素，生长激素(GH)，在人类中表现出显著的昼夜节律。相比之下，没有什么是 知道生长激素敏感度的节律。慢性生长激素升高会导致心脏增大和心力衰竭。生长激素使许多人 诱导胰岛素样生长因子-1(IGF-1)的生物学作用；心肌细胞特异性小鼠模型 IGF-1过表达会导致肥厚型心肌病。我们最近的初步数据显示，每天的时间- 心脏生长激素敏感性的依赖性振荡，这依赖于心肌细胞的生物钟。更多- 此外，CBK心脏表现出更高的生长激素敏感性，心肌细胞IGF-1基因表达增加 肥大和心衰。综上所述，这些观察让我们假设，心肌细胞大约- Dian时钟调节GH敏感性，该机制的破坏使局部IGF-1介导 心肌肥厚和心力衰竭通过增加生长激素敏感性而发生。因此，我们将检验以下假设： 目的1.心肌细胞对生长激素敏感性的昼夜节律调节是维持心脏功能的关键。 心脏功能。我们将确定是否：1a。心肌细胞昼夜节律时钟调节 心脏到生长激素以一天中的时间依赖的方式(生理学)；心肌细胞的遗传破坏 生物钟失衡GH/IGF-1信号轴，从而导致心肌病(病理学)。 目标2.扰乱昼夜节律行为/环境参数(例如，禁食/进食和明/暗 循环)增强心脏GH/IGF-1信号，从而导致收缩功能障碍。我们会 确定是否：2a。昼夜节律行为(例如，禁食/进食周期)或环境(例如， 光/暗周期)影响心脏的GH敏感性和GH/IGF-1信号转导；生长激素/胰岛素样生长因子-1信号的恢复 在心脏中，环境/行为操作可降低对收缩功能障碍的易感性。 我们的研究将确定心肌细胞昼夜节律紊乱与增强有关的机制 心脏GH/IGF-1信号转导。由于年龄相关性CBK心肌病与GH有相似之处 过量，我们的研究可能会形成这样一个新的概念，即生长激素过剩和增强的生长激素敏感性都不会影响生长激素的分泌。 由常见的昼夜节律扰动(例如，饮食、光照、睡眠)引起的心脏功能障碍， 并为未来针对心力衰竭GH/IGF-1信号轴的治疗策略提供了可靠的理论基础。