Atrial fibrillation (AF) is the most common arrhythmia and causes an increased risk of mortality and significant morbidity (such as stroke and heart failure (HF)). The prevalence of AF, especially persistent AF, increases dramatically with aging. However, pharmacological treatment and prevention strategies in the elderly remain ineffective due to a lack of understanding of underlying molecular mechanisms of AF. The c-Jun N-terminal kinase (JNK), a stress-activated protein kinase, is critical in the development of cardiovascular diseases including HF and hypertrophy. Recent studies showed an important role of JNK in downregulation of connexin43 (Cx43). Cx43 is one of the major atrial gap junctional proteins linked to AF stabilization and maintenance. However, the role of JNK in AF development remains unknown. We have intriguing preliminary evidence indicating that significantly enhanced JNK activation in aged rabbit left atria (LA) contributes to marked Cx43 reduction and associated dramatic increase in duration of pacing-induced AF. The objective of this proposal is to further determine the pivotal role of JNK activation in Cx43 reduction that in turn impairs cell coupling and enhances AF in aged LA.
Aim 1 is to assess the functional impact of JNK activation on Cx43 reduction, cell uncoupling and AF maintenance. We will use complementary electrophysiological (optical mapping space constant, 4-electrode microimpedance spectra, cell dye coupling) and biochemical measurements to gain a comprehensive picture of the relationship between JNK-induced Cx43 reduction, impaired cell-coupling in intact LA tissue and myocytes and its impact on AF development in vivo. This will be achieved with [aged rabbit and human hearts,] and cardiac specific JNK transgenic (Tg) mice with JNK activation or inactivation.
Aim 2 is to identify molecular mechanisms of JNK-induced Cx43 reduction including Cx43 gene downregulation and Cx43 protein degradation [in aged rabbit and human LA myocytes.] A series of in vitro gene transfer experiments in isolated atrial myocytes from both aged rabbit and JNK Tg mice will reveal the critical role of JNK isoforms in Cx43 reduction. These experiments integrate important functional measurements and fundamental mechanistic studies. The results will provide important insights into the potential of JNK signaling as a novel therapeutic target for AF prevention and treatment in the elderly. Our long-term goal, understanding the molecular mechanism of AF development in aged hearts with co-existing cardiovascular diseases such as HF, will be greatly advanced by the results of the current proposal.
Atrial fibrillation (AF) is the most common arrhythmia with an increased risk of mortality and a significant morbidity (e.g. stroke, heart failure) in aging population. This proposal is to investigate the pivotal role of c-jun N-terminal kinase (JNK) in connexin43 suppression that in turn enhances AF in aged atria. The results will provide an important basis for further understanding JNK signaling in the development of AF in aged hearts with co-existing cardiovascular disease (e.g. heart failure), and ultimately developing novel effective therapeutic strategies to prevent AF and/or enhance treatment of AF in the elderly.
|Yang, Xiangsheng; Wang, Tiannan; Lin, Xi et al. (2015) Genetic deletion of Rnd3/RhoE results in mouse heart calcium leakage through upregulation of protein kinase A signaling. Circ Res 116:e1-e10|
|Gemel, Joanna; Levy, Andrew E; Simon, Adria R et al. (2014) Connexin40 abnormalities and atrial fibrillation in the human heart. J Mol Cell Cardiol 76:159-68|
|Yan, Jiajie; Thomson, Justin K; Wu, Xiaomin et al. (2014) Novel methods of automated quantification of gap junction distribution and interstitial collagen quantity from animal and human atrial tissue sections. PLoS One 9:e104357|
|Yan, Jiajie; Kong, Wei; Zhang, Qiang et al. (2013) c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias. Cardiovasc Res 97:589-97|