Foxo: Negative Regulator of Cardiac Hypertrophy

与疾病相关的压力触发心脏的肥大性生长， 失败和恶性心律失常的风险显著增加。相比之下， 心脏响应生理需求的生长是适应性的， 并伴有不良后遗症。最近，我们已经证明FoxO转录因子在转录过程中起着重要的作用。 调节心肌细胞生长的关键作用。相反，心脏能够 在各种临床相关情况下大幅收缩，例如 机械支持。肌肉萎缩是一种主动的、需要能量的过程， 泛素连接酶的活化。FoxO转录控制这种“atrogene”反应。 因此，FoxO因子位于多种形式的心脏可塑性的连接处。 在这里，我们提出了一个全面的分析FoxO信号在心脏生长， 重塑我们的中心假设是FoxO转录因子是阴性的， 心脏生长的调节剂。我们建议定义和操纵这些角色， 分子在3种主要形式的心脏重塑：1）病理性肥大， 血液动力学应激; 2）运动的生理性肥大;和3）心脏 心室卸载引起的萎缩。 目的1：检测FoxO转录因子在细胞凋亡过程中的功能相关性。 心脏肥大使用功能获得和功能丧失策略，我们将 定义和操纵FoxO在心脏生长的2种主要形式中的作用，即 病理性和生理性肥大。 目的2：检测FoxO转录因子在细胞凋亡过程中的功能相关性。 心脏萎缩使用异位心脏移植模型，我们将定义 并在心室去负荷的情况下操纵FoxO的作用。 目标3：定义和操纵FoxO影响的机制 钙调神经磷酸酶和Akt活性，病理和生理的两个关键介质， 肥大，分别。我们有证据表明，FoxO激活是一个强大的 抑制钙调神经磷酸酶信号传导的机制，这是导致病理性 逻辑性心脏肥大相比之下，通过PI 3 K/Akt轴的信号传导有助于 生理心脏生长，我们有数据表明，FoxO能够 激活Akt在这里，我们将破译FoxO针对这些主要目标的机制， 病理性（钙调神经磷酸酶）和生理性（Akt）心脏肥大的效应物。

Disease-related stresses trigger hypertrophic growth of the heart that confers markedly increased risk of failure and malignant rhythm disturbance. By contrast, growth of the heart in response to physiological demand is adaptive and not associated with adverse sequelae. Recently, we have shown that FoxO transcription factors play a key role in regulating cardiac myocyte growth. Conversely, the heart is capable of shrinking substantially under a variety of clinically relevant circumstances, such as mechanical support. Muscle atrophy is an active, energy-requiring process requiring activation of ubiquitin ligases. FoxO transcription governs this "atrogene" response. Thus, FoxO factors are situated at the nexus of multiple forms of cardiac plasticity. Here, we propose a comprehensive analysis of FoxO signaling in cardiac growth and remodeling. Our central hypothesis is that FoxO transcription factors are negative regulators of cardiac growth. We propose to define and manipulate the role of these molecules in 3 major forms of cardiac remodeling: 1) pathological hypertrophy stemming from hemodynamic stress; 2) physiological hypertrophy of exercise; and 3) cardiac atrophy from ventricular unloading. Aim 1: To test the functional relevance of FoxO transcription factors during cardiac hypertrophy. Using gain-of-function and loss-of function strategies, we will define and manipulate the actions of FoxO in 2 major forms of cardiac growth, viz. pathological and physiological hypertrophy. Aim 2: To test the functional relevance of FoxO transcription factors during cardiac atrophy. Using a model of heterotopic cardiac transplantation, we will define and manipulate the actions of FoxO in the setting of ventricular unloading. Aim 3: To define and manipulate mechanisms whereby FoxO influences calcineurin and Akt activities, two key mediators of pathological and physiological hypertrophy, respectively. We have evidence that FoxO activation is a robust mechanism of suppressing calcineurin signaling, a major pathway leading to patho- logical cardiac hypertrophy. By contrast, signaling via the PI3K/Akt axis contributes to physiological heart growth, and we have data demonstrating that FoxO is capable of activating Akt. Here, we will decipher mechanisms whereby FoxO targets these major effectors of pathological (calcineurin) and physiological (Akt) cardiac hypertrophy.