Circadian origins of vascular disease in obesity

项目总结 众所周知，肥胖会导致心血管疾病，但其中涉及的机制还不完全 了解和干预打破体重增加和血管疾病之间的联系仍然是至关重要的 治疗的障碍。NOX1衍生的氧化剂上调是血管内皮细胞功能障碍的关键机制 肥胖，但导致这种损害的因素尚不清楚。 心血管生理学中的一个基本概念是血流被调节以服务于新陈代谢 而当肥胖患者的新陈代谢紊乱时，这种关系就会被打破，心血管功能也会出现问题。 心血管功能和代谢需求之间的主要联系是生物钟，一种转录的 调节日常代谢节律并编程心血管基因表达以预测这些变化的网络 改变。小鼠生物钟基因紊乱导致内皮功能障碍和昼夜节律紊乱 人类的生活方式导致心血管疾病的发病率更高。血管时钟是如何变成 疾病的本体论是未知的，并解决了我们在 理解是本应用程序的重点。 来自我们实验室的新数据已经在db/db小鼠中发现了广泛的昼夜节律干扰，这 表现出严重的肥胖和NOX1介导的内皮功能障碍。将这些小鼠培育成Per LUC记者 小鼠显示主动脉昼夜节律几乎消失，周期基因减少80% 时钟调节基因的表达和表达减弱。随后的研究发现夸大了 高血糖作为潜在的昼夜节律干扰物，Galectin-3和Cezanne作为可能的新机制 影响NOX1-eNOS平衡促进血管功能障碍。 基于这些观察，这一提议的核心假设是肥胖导致血管 继发于血管生物钟功能丧失的疾病。我们将在体内测试假说 具有昼夜节律控制成分的新型肥胖动物模型和体外识别新的 可能成为肥胖血管疾病治疗靶点的细胞机制。

PROJECT SUMMARY It is well known that obesity drives cardiovascular disease, but the mechanisms involved are incompletely understood and interventions that break the links between weight gain and vascular disease remain a critical barrier to treatment. Upregulation of NOX1-derived oxidants is a key mechanism of endothelial dysfunction in obesity but the factors precipitating this impairment are unknown. A fundamental concept in cardiovascular physiology is that blood flow is regulated to service metabolism and when metabolism is deranged in obesity, this relationship breaks down and cardiovascular function falters. A major link between cardiovascular function and metabolic demand is the circadian clock, a transcriptional network that regulates daily metabolic rhythms and programs cardiovascular gene expression to anticipate these changes. Genetic disruption of the clock in mice results in endothelial dysfunction and disruptive circadian lifestyles in humans leads to a higher incidence of cardiovascular disease. How the vascular clock becomes disrupted and the subsequent ontology of disease are unknown and resolving these critical deficits in our understanding is the focus of this application. New data from our laboratories have identified extensive circadian disruption in the db/db mouse, which exhibits profound obesity and NOX1-mediated endothelial dysfunction. Breeding these mice to a per luc reporter mouse revealed near abrogation of circadian rhythms in the aorta along with an 80% reduction in cyclic gene expression and diminished expression of clock regulated genes. Subsequent studies identified exaggerated hyperglycemia as a potential circadian disruptor and Galectin-3 and Cezanne as novel mechanisms that may influence NOX1 – eNOS balance to promote vascular dysfunction. Based on these observations, the core hypothesis of this proposal is that obesity causes vascular disease secondary to loss of function of the vascular circadian clock. We will test hypothesis in vivo in novel animal models of obesity with manipulated components of circadian control and in vitro to identify new cellular mechanisms that may be targets for the treatment of vascular disease in obesity.