Abstract 19557: Novel Stress Signaling JNK Regulates Pro-arrhythmic Molecular CaMKIIδ Activity and Expression in Aged Human Atrium
The c-Jun N terminal kinase (JNK) is an important member of the MAP kinases family, activated in response to stress and implicated in the development of cardiovascular diseases (CVDs). We have previously shown that JNK plays a pivotal role in development of atrial arrhythmia in aged hearts. However, the underlying mechanism remains incompletely understood. Accumulating evidence suggests that CaMKIIδ is another critical kinase in the development of arrhythmias and CVDs. In human atrial tissue, we discovered that enhanced phosphorylation of JNK (JNK-P) was associated with an increased ratio of phosphorylation of CaMKIIδ Thr286 (CaMKII-P) to total CaMKIIδ (immunoblotting assay) with increasing age (19-82yrs; n=12), while the level of CaMKIIδ mRNA expression (qPCR) was also up-regulated. To further characterize the JNK-CaMKIIδ relationship, we used a unique HL1 atrial myocyte line. CaMKIIδ activation status was assessed using a specific CaMKIIδ-P antibody (immunoblotting assay) and a CaMKIIδ biosensor camui (FRET imaging assay). We found that atrial myocytes treated with JNK activator anisomysin (24hrs) exhibited significantly increased CaMKIIδ-P (56% vs sham controls; p<0.01; n=4,4) that was associated with markedly elevated JNK-P. In JNK activated live HL-1 myocytes, the activation of CaMKII (ratio of CFP to YFP fluorescence (FCFP/FYFP)) was increased by 35% (vs sham controls; p<0.05; n=4,4 monolayers). This suggests that JNK activation caused enhanced CaMKII activation in atrial myocytes. Overexpression of inactivated JNK2 (dominant negative; JNK2dn) attenuated JNK-induced CaMKIIδ activation (both CaMKII-P and camui FRET assays). Moreover, we found that the amount of CaMKIIδ protein and mRNA expressions in JNK-activated myocytes was up-regulated by 103% and 75%, respectively (p<0.05; n=3,3). Finally, overexpressed JNK2dn markedly suppressed JNK-induced CaMKIIδ up-regulation at both protein and mRNA levels (n=4,4). In conclusion, we report here for the first time that the novel stress signaling JNK regulates not only activity but also expression of the pro-arrhythmic signaling molecular CaMKIIδ in aged atrium. Modulation of JNK signaling could be a novel therapeutic approach to prevent and treat arrhythmias and CVDs in the elderly.
Author Disclosures: X. Wu: None. W. Zhao: None. E. Corrillo: None. W. Chen: None. J. Yan: None. D.M. Bers: None. S.L. Robia: None. X. Ai: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.