Abstract 088: JNK2 Impairs Atrial Conduction And Enhances Arrhythmogenicity In Mouse Atria

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The c-Jun N-terminal kinase (JNK) is a stress-activated kinase that is important in the development of cardiovascular diseases. We have previously shown that enhanced JNK activation was associated with suppressed gap junction Cx43, slow conduction, and increased atrial fibrillation (AF) in aged rabbit left atrium (LA). In an atrial cellular model (HL-1), we further demonstrated that JNK activation downregulated Cx43 and enhanced arrhythmogenicity. However, direct evidence for JNK inducing atrial arrhythmia in vivo is lacking. In the present study, we found that JNK activator anisomycin (aniso) treatment in wild-type (WT) mouse in vivo resulted in a 30% decrease in Cx43 protein in LA vs that of vehicle-treated WT LA (p<0.001; n=4, 6; each sample contained mixed LAs from 5 mice). From optical mapping recordings in the intact LA, conduction velocity (CV) in aniso-treated WT mice slowed by 36% (30±2 vs. 47±1 cm/sec in vehicle-treated WT, pacing cycle length (CL) = 100ms, p<0.01; n=4, 3). Additional in vivo treatment with SP600125 (a specific JNK inhibitor) reversed aniso-induced Cx43 suppression (n=3) and CV slowing (50±2 cm/sec; n=6) as compared with WT LA treated with aniso alone (p<0.001). Moreover, we assessed atrial arrhythmia susceptibility in vivo using burst pacing delivered via an octapolar cardiac catheter. JNK activated hearts exhibited an increased incidence of pacing-induced AF (13%; n=7), while no AF was induced in WT-vehicle mice (n=4). To further confirm the specific role of JNK activation in atrial arrhythmogenicity, JNK2 (one of the cardiac JNK isoforms) knockout mice (JNK2KO) were treated with aniso in vivo. Similar to the effect of JNK inhibition by SP600125, JNK2 knockout prevented aniso-induced Cx43 suppression (n=3) and slowing of CV (47±1cm/sec, CL=100ms; n=4) compared with aniso-treated WT (p<0.05 & p<0.001, respectively). Furthermore, a dramatically decreased susceptibility to pacing-induced AF (1.7%; n=6) was found in aniso-treated JNK2KO vs aniso-treated WT mice. In conclusion, our results strongly suggest that JNK, especially JNK2, activation contributes to impaired cell-cell communication that in turn promotes AF development. Modulation of JNK2 could be a novel therapeutic approach to prevent and treat AF in the elderly.