JNK Regulation of Cx43 Expression and Cardiac Remodeling

描述（由申请人提供）：心力衰竭（HF）是美国死亡和行动不便的主要原因，并与收缩功能障碍和危及生命的心律失常相关。参与衰竭心脏病理重塑的信号机制尚不完全清楚。应激激活的MAP激酶（SAPKs）途径之一，cJun n -末端激酶（JNK），在HF的发展过程中被认为是介导多种应激反应的重要信号传导成分。我们在前期研究中发现，JNK在转基因心脏中特异性激活，导致心脏病理重构，心脏连接蛋白43 （cardiac connexin43, Cx43）显著下调，导致动物过早猝死。而在培养细胞中，JNK的激活也会导致肥大、Cx43表达和细胞-细胞耦合的丧失，这一效应可以通过阻断JNK活性来减弱。我们的发现首次揭示了应激相关的细胞信号通路对心脏中Cx43表达的负调控，并使我们假设JNK介导的信号通路是衰竭心脏病理重塑的重要途径，涉及Cx43的下调。因此，本研究的重点是确定JNK介导心肌细胞Cx43表达下调的分子和细胞机制，并确定JNK信号通路在涉及细胞间通讯的病理重塑中的生理意义。具体而言，本研究将实现以下目标：1)。建立JNK通路在心肌细胞Cx43表达调控中的具体作用。2）. 确定JNK介导的肌细胞Cx43调控的分子机制。3）. 利用新建立的可诱导转基因模型，在分子、细胞和全心水平上建立JNK激活与心脏重构的时间相关性。4）. 探讨JNK诱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。本研究可能为心衰发病过程中应激介导的信号机制提供更好的理解，并为该疾病的治疗提供潜在的新途径。

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.