JNK Regulation of Cx43 Expression and Cardiac Remodeling

描述(由申请人提供)：心力衰竭(HF)是美国死亡和静止的主要原因，并与收缩功能障碍和危及生命的心律失常有关。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)之一的cJun氨基末端激酶(JNK)被认为是介导多种应激反应的重要信号成分，参与心力衰竭的发生发展。在我们的初步研究中，我们发现转基因心脏中JNK的特异性激活导致心脏病理重塑，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、Cx43表达和细胞-细胞偶联的丧失，这种作用可以通过阻断JNK的活性来减弱。我们的发现首次揭示了一种与应激相关的细胞信号通路参与心脏Cx43表达的负调控，并导致我们假设JNK介导的信号转导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下调心肌细胞Cx43表达的分子和细胞机制，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学意义。具体地说，拟议的研究将实现以下目标：1)。目的：探讨JNK通路在心肌细胞Cx43表达调控中的特殊作用。2)。目的：探讨JNK调控心肌细胞Cx43的分子机制。3)。目的：利用新建立的可诱导转基因模型，在分子、细胞和全心脏水平上建立JNK激活与在体心脏重构之间的时间相关性。4)。目的：探讨JNK诱导的病理重塑在心力衰竭和早逝发生发展中的生理基础和功能意义。这项拟议的研究可能会更好地理解心力衰竭发病过程中应激介导的信号机制，并导致潜在的治疗心力衰竭的新途径。

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.