Foxo: Negative Regulator of Cardiac Hypertrophy

描述（由申请人提供）：疾病相关应激触发心脏肥大性生长，导致心力衰竭和恶性心律紊乱的风险显著增加。相比之下，心脏响应生理需求的生长是适应性的，与不良后遗症无关。最近，我们发现FoxO转录因子在调节心肌细胞生长中起关键作用。相反，心脏能够在各种临床相关情况下（例如机械支持）大幅收缩。肌肉萎缩是一个主动的、需要能量的过程，需要泛素连接酶的激活。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信号在心脏生长和重塑。我们的中心假设是FoxO转录因子是心脏生长的负调节因子。我们建议定义和操纵这些分子在3种主要形式的心脏重塑中的作用：1）由血液动力学应激引起的病理性肥大; 2）运动引起的生理性肥大; 3）心室卸载引起的心脏萎缩。目的1：探讨FoxO转录因子在心肌肥厚中的作用。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，即病理性和生理性肥大中的作用。目的2：检测FoxO转录因子在心肌萎缩过程中的功能相关性。使用异位心脏移植模型，我们将定义和操纵FoxO在心室去负荷设置中的作用。目标3：定义和操纵FoxO影响钙调神经磷酸酶和Akt活性的机制，这两种活性分别是病理性和生理性肥大的关键介质。我们有证据表明FoxO激活是抑制钙调神经磷酸酶信号传导的一种强大机制，钙调神经磷酸酶信号传导是导致病理性心脏肥大的主要途径。相比之下，通过PI 3 K/Akt轴的信号传导有助于生理性心脏生长，并且我们有数据表明FoxO能够激活Akt。在这里，我们将破译机制，FoxO的目标，这些主要效应的病理性（钙调神经磷酸酶）和生理性（Akt）心脏肥大。公共卫生相关性：预计到2020年，心血管疾病将成为全球最常见的死亡原因。最近的研究表明，FoxO转录因子位于多种形式的心脏可塑性的联系。通过确定它们在病理性心脏生长和萎缩中的作用，我们将采取可能导致预防人类心力衰竭的新策略的步骤。

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.