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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-E (02))
Program Officer
Krull, Holly
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Loyola University Chicago
Schools of Medicine
United States
Zip Code
Yan, Jiajie; Thomson, Justin K; Zhao, Weiwei et al. (2018) The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart. J Mol Cell Cardiol 114:105-115
Hou, Xiaoying; Du, Hongzhi; Quan, Xingping et al. (2018) Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway. Front Pharmacol 9:21
Gao, Xianlong; Wu, Xiaomin; Yan, Jiajie et al. (2018) Transcriptional regulation of stress kinase JNK2 in pro-arrhythmic CaMKII? expression in the aged atrium. Cardiovasc Res 114:737-746
Yan, Jiajie; Thomson, Justin K; Zhao, Weiwei et al. (2018) Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia. J Am Coll Cardiol 71:1459-1470
Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K et al. (2018) Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circ Res 122:821-835
Zhang, Rui; Zhang, Guoying; Xiang, Binggang et al. (2017) TRAF3 negatively regulates platelet activation and thrombosis. Sci Rep 7:17112
Hood, Ashleigh R; Ai, Xun; Pogwizd, Steven M (2017) Regulation of cardiac gap junctions by protein phosphatases. J Mol Cell Cardiol 107:52-57
Ai, Xun; Yan, Jiajie; Carrillo, Elena et al. (2016) The Stress-Response MAP Kinase Signaling in Cardiac Arrhythmias. Rev Physiol Biochem Pharmacol 172:77-100
Ai, Xun (2015) SR calcium handling dysfunction, stress-response signaling pathways, and atrial fibrillation. Front Physiol 6:46
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

Showing the most recent 10 out of 17 publications