Transcriptional regulation of stress kinase JNK2 in pro-arrhythmic CaMKIIdelta expression in the aged atrium Journal Article

Authors: Gao, X; Wu, X; Yan, J.; Zhang, J; Zhao, W; DeMarco, D.; Zhang, Y; Bakhos, M; Mignery, G.; Sun, J; Li, Z; Fill, M.; Ai, X
Article Title: Transcriptional regulation of stress kinase JNK2 in pro-arrhythmic CaMKIIdelta expression in the aged atrium
Abstract: Aims: c-jun N-terminal kinase (JNK) is a critical stress response kinase that activates in a wide range of physiological and pathological cellular processes. We recently discovered a pivotal role of JNK in the development of atrial arrhythmias in the aged heart, while cardiac CaMKIIdelta, another pro-arrhythmic molecule, was also known to enhance atrial arrhythmogenicity. Here, we aimed to reveal a regulatory role of the stress kinase JNK2 isoform on CaMKIIdelta expression. Methods and results: Activated JNK2 leads to increased CaMKIIdelta protein expression in aged human and mouse atria, evidenced from the reversal of CaMKIIdelta up-regulation in JNK2 inhibitor treated wild-type aged mice. This JNK2 action in CaMKIIdelta expression was further confirmed in HL-1 myocytes co-infected with AdMKK7D-JNK2, but not when co-infected with AdMKK7D-JNK1. JNK2-specific inhibition (either by a JNK2 inhibitor or overexpression of inactivated dominant-negative JNK2 (JNK2dn) completely attenuated JNK activator anisomycin-induced CaMKIIdelta up-regulation in HL-1 myocytes, whereas overexpression of JNK1dn did not. Moreover, up-regulated CaMKIIdelta mRNA along with substantially increased phosphorylation of JNK downstream transcription factor c-jun [but not activating transcription factor2 (ATF2)] were exhibited in both aged atria (humans and mice) and transiently JNK activated HL-1 myocytes. Cross-linked chromatin-immunoprecipitation assays (XChIP) revealed that both c-jun and ATF2 were bound to the CaMKIIdelta promoter, but significantly increased binding of c-jun only occurred in the presence of anisomycin and JNK inhibition alleviated this anisomycin-elevated c-jun binding. Mutated CaMKII consensus c-jun binding sites impaired its promoter activity. Enhanced transcriptional activity of CaMKIIdelta by anisomycin was also completely reversed to the baseline by either JNK2 siRNA or c-jun siRNA knockdown. Conclusion: JNK2 activation up-regulates CaMKIIdelta expression in the aged atrium. This JNK2 regulation in CaMKIIdelta expression occurs at the transcription level through the JNK downstream transcription factor c-jun. The discovery of this novel molecular mechanism of JNK2-regulated CaMKII expression sheds new light on possible anti-arrhythmia drug development.
Journal Title: Cardiovascular research
Volume: 114
Issue: 5
ISSN: 1755-3245; 0008-6363
Publisher: Unknown  
Journal Place: England
Date Published: 2018
Start Page: 737
End Page: 746
Language: eng
Notes: LR: 20180328; GR: R01 AA024769/AA/NIAAA NIH HHS/United States; GR: R01 HL113640/HL/NHLBI NIH HHS/United States; JID: 0077427; 2016/06/01 00:00 [received]; 2018/01/18 00:00 [accepted]; 2018/01/24 06:00 [pubmed]; 2018/01/24 06:00 [medline]; 2018/01/24 06:00 [entrez]; ppublish