Foxo: Negative Regulator of Cardiac Hypertrophy

描述（由申请人提供）：疾病相关的压力会引发心脏肥厚生长，从而显著增加心力衰竭和恶性心律失常的风险。相比之下，心脏的生长响应生理需求是适应性的，与不良后遗症无关。最近，我们已经证明FoxO转录因子在调节心肌细胞生长中起关键作用。相反，在各种临床相关情况下，如机械支持下，心脏能够大幅收缩。肌肉萎缩是一个活跃的、需要能量的过程，需要激活泛素连接酶。FoxO转录控制着这种“atrogene”反应。因此，FoxO因子处于多种形式的心脏可塑性的联系中。在这里，我们提出了FoxO信号在心脏生长和重塑的综合分析。我们的中心假设是FoxO转录因子是心脏生长的负调节因子。我们建议定义和控制这些分子在三种主要形式的心脏重构中的作用：1)由血流动力学应激引起的病理性肥大；2)生理性运动肥大；3)心室卸荷引起的心肌萎缩。目的1：检测FoxO转录因子在心肌肥厚过程中的功能相关性。利用功能获得和功能丧失策略，我们将定义和操纵FoxO在心脏生长的两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转录因子在心肌萎缩中的功能相关性。使用异位心脏移植模型，我们将定义和操纵FoxO在心室卸载设置中的作用。目的3：定义和操纵FoxO影响钙调磷酸酶和Akt活性的机制，钙调磷酸酶和Akt分别是病理性和生理性肥大的两种关键介质。我们有证据表明FoxO激活是抑制钙调磷酸酶信号传导的强大机制，钙调磷酸酶信号传导是导致病理性心脏肥厚的主要途径。相比之下，通过PI3K/Akt轴的信号传导有助于生理性心脏生长，我们有数据表明FoxO能够激活Akt。在这里，我们将破译FoxO针对病理性（钙调磷酸酶）和生理性（Akt）心肌肥厚这些主要效应因子的机制。公共卫生相关性：预计到2020年，心血管疾病将成为全世界最常见的死亡原因。最近的研究表明，FoxO转录因子位于心脏可塑性的多种形式的联系。通过确定它们在病理性心脏生长和萎缩中的作用，我们将采取措施，可能导致新的策略来预防人类心力衰竭。

DESCRIPTION (provided by applicant): 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 sequalae. 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. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases are predicted to be the most common cause of mortality worldwide by the year 2020. Recent studies reveal that FoxO transcription factors are situated at the nexus of multiple forms of cardiac plasticity. By determining their role in pathological cardiac growth and atrophy, we will take steps that may lead to novel strategies to prevent heart failure in humans.