A novel anti-hypertrophic pathway in the heart

描述(由申请人提供)：心脏肥大是由各种生理和病理生理条件引起的。然而，持续性的心肌肥厚在导致心力衰竭或猝死的适应性不良心脏重塑的发生中起着重要作用。尽管多条信号通路已被证明与肥厚的发生有关，但对心脏中的抗肥厚通路知之甚少。FOXO3a是一种转录因子。最近的研究表明，它可以负向调节心肌肥厚。心肌肥厚可由包括活性氧(ROS)在内的信号分子介导。细胞内ROS的平衡受过氧化氢酶等抗氧化酶的调节。我们的初步研究表明，FOXO3a能够上调心肌细胞中过氧化氢酶的表达。此外，FOXO3a基因敲除后，ROS水平升高，心肌细胞肥大。给予抗氧化剂可以减轻FOXO3a基因敲除后的肥大。这些观察结果使我们提出假设：“FOXO3a对过氧化氢酶的调节构成了心脏中的一条抗肥大途径”。我们将在以下具体目标下通过研究来检验这一点。AIM-1将确定FOXO3a是否通过靶向细胞模型中的过氧化氢酶来调节肥大。AIM-2将阐明FOXO3a-过氧化氢酶途径在动物模型中是否被激活。AIM-3将表征FOXO3a-过氧化氢酶途径是否受miRNAs调控。这项研究不仅有助于我们了解FOXO3a-过氧化氢酶在调节心肌肥厚中的作用，而且可能导致进一步的研究，以探索该通路作为生物靶点对适应性不良肥厚和心力衰竭的介入治疗的有益作用。公共卫生相关性：持续性心肌肥厚已被证明在导致心力衰竭或猝死的适应性不良心脏重塑的发生中起着重要作用。本项目旨在研究FOXO3a对过氧化氢酶的转录调控是否构成心脏的抗肥大途径。该项目的成功完成将为探索该通路在控制肥厚和心力衰竭方面的有益作用提供重要信息。

DESCRIPTION (provided by applicant): Summary Cardiac hypertrophy occurs in response to a variety of physiological and pathophysiological conditions. However, sustained cardiac hypertrophy plays an important role for the development of maladaptive cardiac remodeling leading to heart failure or sudden death. Although multiple signaling pathways have been shown to be implicated in the development of hypertrophy, it is poorly understood regarding the anti-hypertrophic pathways in the heart. FOXO3a is a transcriptional factor. Most recent studies show that it can negatively regulate cardiac hypertrophy. Cardiac hypertrophy can be mediated by the signaling molecules including reactive oxygen species (ROS). The cellular equilibrium of ROS is regulated by the antioxidant enzymes such as catalase. Our preliminary studies showed that FOXO3a is able to upregulate the expression of catalase in cardiomyocytes. Furthermore, knockdown of FOXO3a led to an increased level of ROS and cardiomyocyte hypertrophy. Administration of the antioxidant could attenuate hypertrophy upon FOXO3a knockdown. These observations lead us to hypothesize that "the regulation of FOXO3a on catalase constitutes an anti-hypertrophic pathway in the heart''. We will test this through studies under the following specific aims. Aim-1 will determine whether FOXO3a regulates hypertrophy by targeting catalase in the cellular model. Aim-2 will elucidate whether FOXO3a-catalase pathway is activated in the animal model. Aim-3 will characterize whether FOXO3a-catalase pathway is regulated by miRNAs. This proposed study will not only help us understand the role of FOXO3a-catalase in regulating cardiac hypertrophy, but could lead to further studies to explore the beneficial effect of this pathway as a biological target for the interventional treatment of maladaptive hypertrophy as well as heart failure. PUBLIC HEALTH RELEVANCE: Sustained cardiac hypertrophy has been proved to play an important role for the development of maladaptive cardiac remodeling leading to heart failure or sudden death. This project is to characterize whether the transcriptional regulation of FOXO3a on catalase constitutes an anti-hypertrophic pathway in the heart. The successful completion of project will provide important information for exploring the beneficial effects of this pathway in controlling hypertrophy as well as heart failure.