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Cardiovasc Res. 2013 Mar 1;97(3):589-97. doi: 10.1093/cvr/cvs366. Epub 2012 Dec 14.

c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias.

Author information

1
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Abstract

AIMS:

c-Jun N-terminal kinase (JNK) activation is implicated in cardiovascular diseases and ageing, which are linked to enhanced propensity to atrial fibrillation (AF). However, the contribution of JNK to AF remains unknown. Thus, we assessed the role of JNK in remodelling of gap junction connexin43 (Cx43) and development of AF.

METHODS AND RESULTS:

AF induction, optical mapping, and biochemical assays were performed in young and aged New Zealand white rabbit left atria (LA) and cultured HL-1 atrial cells. In aged rabbit LA, pacing-induced atrial arrhythmias were dramatically increased and conduction velocity (CV) was significantly slower compared with young controls. Aged rabbit LA contained 120% more activated JNK and 54% less Cx43 than young LA. Young rabbits treated with JNK activator anisomycin also exhibited increased pacing-induced atrial arrhythmias and reduced Cx43 (by 34%), similar to that found in aged LA. In HL-1 cell cultures, anisomycin treatment for 16 h led to 42% reduction in Cx43, 24% reduction in CV, and an increased incidence of irregular rapid spontaneous activities. These effects were prevented by a specific JNK inhibitor, SP600125. Moreover, a 63% reduction in Cx43 after anisomycin treatment for 24 h led to further slowed CV (by 41%) along with dramatically increased irregular rapid spontaneous activity and highly discontinuous conduction. These JNK-induced functional abnormalities were completely reversed by overexpressed exogenous wild-type Cx43, but not by inactive Cx43.

CONCLUSION:

JNK activation contributes to Cx43 reductions that promote development of AF. Modulation of JNK may be a potential novel therapeutic approach to prevent and treat AF.

PMID:
23241357
PMCID:
PMC3567788
DOI:
10.1093/cvr/cvs366
[Indexed for MEDLINE]
Free PMC Article

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