JNK Regulation of Cx43 Expression and Cardiac Remodeling

JNK 对 Cx43 表达和心脏重构的调节

• 批准号: 6937159
• 负责人: Yibin Wang
• 金额: $ 33.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937159
• 关键词: JUN kinase; cardiac myocytes; confocal scanning microscopy; electrophysiology; enzyme activity; enzyme induction /repression; fluorescence microscopy; fluorescent dye /probe; gap junctions; gene expression; genetic regulatory element; genetically modified animals; heart electrical activity; heart failure; heart metabolism; intercellular connection; isozymes; laboratory mouse; membrane channels; molecular pathology; physiologic stressor; posttranslational modifications; tissue /cell culture; video microscopy; western blottings

DESCRIPTION (provided by applicant): Heart failure (HF) is the leading cause of mortality and immobility in the US, and is associated with contractile dysfunction and life-threatening arrhythmia. Signaling mechanisms involved in the pathological remodeling in the failing heart are not yet fully understood. One of the stress-activated MAP kinases (SAPKs) pathways, the cJun N-terminal kinases (JNK), has been implicated as an important signaling component mediating a variety of stress responses in the development of HF. In our preliminary study, we discovered that specific activation of JNK in transgenic hearts caused pathological remodeling in heart with significant downregulation of cardiac connexin43 (Cx43) and animals died from premature sudden death. While in cultured cells, activation of JNK also resulted in hypertrophy and the loss of Cx43 expression and cell-cell coupling, an effect that can be attenuated by blocking JNK activity. Our findings implicated, for the first time, a stress-related cellular signaling pathway in the negative regulation of Cx43 expression in heart, and led to us to hypothesize that JNK mediated signaling is an important pathway for pathological remodeling in failing heart, involving down-regulation of Cx43. Accordingly, the main focus of the current proposal is to determine the molecular and cellular mechanisms of JNK mediated down-regulation of Cx43 expression in cardiac myocytes and to establish the physiological significance of JNK signaling pathway in pathological remodeling involving inter-cellular communication. Specifically, the proposed study will accomplish the following aims: 1). To establish the specific role of JNK pathway in the regulation of Cx43 expression in cardiomyocytes. 2). To determine the molecular mechanism underlying JNK mediated Cx43 regulation in myocytes. 3). To establish the temporal correlation between JNK activation and cardiac remodeling in vivo at molecular, cellular and whole heart levels using a newly established inducible transgenic model. 4). To determine the physiological basis and functional significance of JNK induced pathological remodeling in the development of heart failure and premature death. The proposed study may provide better understanding to stress-mediated signaling mechanisms in the patholgenic process of heart failure and leads to potential new therapeutic avenues for the disease.

描述（由申请人提供）：心力衰竭（HF）是美国死亡和不动的主要原因，并与收缩功能障碍和危及生命的心律失常相关。衰竭心脏病理性重构的信号机制尚未完全清楚。应激激活的MAP激酶（SAPKs）途径之一，cJun N-末端激酶（JNK），已经被认为是在HF的发展中介导各种应激反应的重要信号传导组分。在我们的前期研究中，我们发现转基因心脏中JNK的特异性激活导致心脏病理性重构，心脏连接蛋白43（Cx43）显著下调，动物死于过早猝死。而在培养的细胞中，JNK的激活也导致肥大和Cx43表达和细胞-细胞偶联的丧失，这种作用可以通过阻断JNK活性来减弱。我们的研究结果暗示，第一次，在心脏中的Cx43表达的负调控的应激相关的细胞信号通路，并导致我们假设JNK介导的信号转导是一个重要的途径，在衰竭的心脏，涉及下调Cx43的病理性重构。因此，当前建议的主要焦点是确定JNK介导的心肌细胞中Cx43表达下调的分子和细胞机制，并建立JNK信号通路在涉及细胞间通讯的病理重构中的生理意义。具体而言，拟议的研究将实现以下目标：1）。探讨JNK信号通路在心肌细胞Cx43表达调控中的作用。2）。探讨JNK介导的Cx43调节的分子机制。3）。利用一种新建立的诱导型转基因动物模型，在分子、细胞和整体心脏水平上建立JNK激活与心脏重构之间的时间相关性。4）。探讨JNK介导的病理性重构在心力衰竭和早死发生中的生理基础和功能意义。这项研究可能有助于更好地理解心力衰竭发病过程中应激介导的信号传导机制，并为心力衰竭的治疗开辟新的途径。