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Age‐dependent increased activation of c‐Jun N‐terminal kinase is associated with decreased connexin43 in vivo
Author(s) -
Jones Sandra Anne,
Lancaster Matthew Kenneth
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1446-b
Subject(s) - in vivo , phosphorylation , kinase , western blot , ageing , nerve conduction velocity , gap junction , medicine , myocyte , protein kinase a , endocrinology , chemistry , intracellular , endogeny , biology , biochemistry , gene , microbiology and biotechnology
Connexin43 (Cx43) is the predominant cardiac gap junctional protein, critical for maintaining electrical conduction: a substantial reduction of Cx43 protein can instigate conduction abnormalities and arrhythmic events. We tested the hypothesis that during cardiac ageing in vivo , intercellular conduction would decrease as total endogenous Cx43 protein expression decreased, concurrently with increased activation of c‐jun N‐terminal kinase (JNK). Right atrial muscle from guinea pigs in the age range of 1 day to 38 months was examined using Western blot and confocal immunofluorescence. The area of the intercalated disc increased during ageing, accompanied by a 75% reduction of total endogenous Cx43 protein expression, 0.09±0.03μgCx43/μg total protein at 38 months compared with 0.40±0.05 at 1 day (n=5; ANOVA p<0.001). The 38 month animal possessed mostly phosphorylated Cx43 (P‐Cx43) at the intercalated discs (0.99±0.03, P‐Cx43:total Cx43) compared with the 1 day (0.48±0.02) (n=5; ANOVA p<0.001). Associated with the phosphorylation of Cx43 protein is the stress‐activated JNK (or phosphorylated JNK expressed as a ratio to non‐phosphorylated JNK), increased from 0.14±0.01 in the 1 day to 0.68±0.05 in the 38 month animal (n=5; ANOVA p<0.001). The conduction velocity of the action potential across the right atrial muscle slowed to 0.30±0.01m/s at 38 months from 0.38±0.01m/s at 1 month. Our observations suggest uncoupling of right atrial myocytes in aged tissue is mediated by the stress‐induced JNK signalling pathway, implicated with the concurrent substantial loss of Cx43 protein from the intercalated discs and diminished electrical communication.