Abstract 2875: Alterations in Beta-catenin, a Constitution of Adhesion Junctions Precede the Gap Junction Connexin43 Remodeling During the Development of Heart Failure
The intercalated disc contains different junctional complexes (adhesion junctions and gap junctions) that enable the myocardium to function as a syncytium. The adhesion junctions are organized to mediate normal mechanical coupling between cardiomyocytes and play a key role in the formation and stability of gap junctions. The remodeling of ventricular gap junction connexin (Cx)43 is a prominent feature of arrhythmogenesis in diseased myocardium. In addition, the enhancement of Cx43 transcript accumulation is reported to be mediated through Wnt-dependent accumulation of beta-catenin and trancriptional activation via a beta-catenin/Tcf nuclear complex. To investigate alterations in beta-catenin/Cx43 and arrhythmogenesis during the development heart failure, we used UM-X7.1 cardiomyopathic hamster hearts. At age 10wk (hypertrophic stage), ~10% of cardiomyopathic hamsters died suddenly without heart failure, and VT/VF was inducible in ~30% hamsters. Although there was no significant difference in Cx43 expression (mRNA and protein), the protein expression level of beta-catenin in nuclear fraction was remarkably decreased (~45% decrease) compared with age-matched golden hamsters. Electron microscopy revealed that density linking cell-cell adhesion was irregular and unclearly defined, and filamentous structures attached to electron-dense components arranged in disorder. At age 20wk (heart failure stage), left ventricular Cx43 protein expression was significantly decreased (~50% decrease) with a remarkable increase of Ser255-phospholylated Cx43 protein expression (~60% increase), which is known to inhibit cell-cell communication. The lethal ventricular arrhythmias were inducible in all cardiomyopathic hamsters. These results suggest that the translocation of beta-catenin from nuclear to membrane fraction precedes the gap junction remodeling, resulting in quantitative and qualitative alterations in Cx43. In conclusions, changes of adhesion junctions might play an important role in the gap junction remodeling and contribute to an arrhythmogenesis in failing heart.