A novel anti-hypertrophic pathway in the heart

描述（由申请人提供）：摘要心脏肥大是对各种生理和病理生理条件的反应。然而，持续的心肌肥厚在适应不良的心脏重构的发展中起重要作用，导致心力衰竭或猝死。虽然多种信号通路已被证明与肥大的发展有关，但对心脏中的抗肥大通路知之甚少。FOXO 3a是一种转录因子。最近的研究表明，它可以负性调节心肌肥厚。心肌肥大可由包括活性氧（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FOXO 3a能够上调心肌细胞中过氧化氢酶的表达。此外，敲低FOXO 3a导致ROS水平增加和心肌细胞肥大。给予抗氧化剂可在FOXO 3a敲低后减弱肥大。这些观察结果使我们假设“FOXO 3a对过氧化氢酶的调节构成了心脏中的抗肥大途径”。我们将通过以下具体目标下的研究来检验这一点。Aim-1将确定FOXO 3a是否通过靶向细胞模型中的过氧化氢酶来调节肥大。目的-2将阐明FOXO 3a-过氧化氢酶通路是否在动物模型中被激活。目的-3将表征FOXO 3a-过氧化氢酶途径是否受miRNA调控。这项拟议的研究不仅有助于我们了解FOXO 3a-过氧化氢酶在调节心脏肥大中的作用，而且可能导致进一步的研究，以探索该途径作为适应不良肥大和心力衰竭介入治疗的生物靶点的有益作用。公共卫生相关性：持续性心肌肥厚已被证明在适应不良的心脏重构的发展中起重要作用，导致心力衰竭或猝死。本项目旨在研究FOXO 3a对过氧化氢酶的转录调控是否构成心脏中的抗肥大途径。该项目的成功完成将为探索该通路在控制心肌肥厚以及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.