Progressive age-associated activation of JNK associates with conduction disruption in the aged atrium.

Connexin43 (Cx43) is critical for maintaining electrical conduction across atrial muscle. During progressive aging cardiac conduction slows and becomes susceptible to disruption, predisposing to arrhythmias. Changes in Cx43 protein expression, or its phosphorylation status, can instigate changes in the conduction of the cardiac action potential. Our study investigated whether increased levels of activated c-jun N-terminal kinase (JNK) is the mechanism responsible for the decline of Cx43 protein and intercellular communication during progressive aging. We examined right atrial muscle from guinea pigs between 1 day and 38 months of age. The area of the intercalated disc increased with age concurrent with a 75% decline in total C43 protein expression and spatial re-organisation of the remaining protein. An age-dependent increase in activated-JNK correlated with a rise in phosphorylated Cx43. The data also correlated with slowing of the action potential conduction velocity across the right atria from 0.38±0.01 m/s at 1 month of age to 0.30±0.01 m/s at 38 months of age. The JNK activator anisomycin increased levels of activated JNK in myocytes and reduced Cx43 protein expression paralleling the aging effect The JNK inhibitor SP600125, was found to eradicate almost all trace of Cx43 protein from the intercalating discs. We conclude that in vivo activation of JNK increases with age leading to the loss of Cx43 protein from atrial myocytes. This progressive loss results in impaired conduction and is likely to contribute to the increasing risk of atrial arrhythmias with advancing age.