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.
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