Abstract 17195: Cardiac-Restricted Deletion of Plakoglobin Results in Progressive Cardiomyopathy and Activation of Akt/Beta-Catenin Signaling
Background: Mutations in plakoglobin (PG) gene have been identified in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, mechanisms underlying PG dysfunction involved in the pathogenesis of ARVC remain poorly understood. PG is a component of both desmosomes and adherens junctions located at intercalated disc (ICD) of cardiomyocytes where it functions to link cadherins to the cytoskeleton. In addition, PG is thought to function as a signaling protein via its ability to modulate Wnt signaling pathway.
Methods: We generated an inducible cardiac-restricted knockout (CKO) of the PG gene in mice, and performed a series of experiments to examine the role of PG in the heart, and compared with WT.
Results: The PG CKO mice exhibited progressive loss of cardiac myocytes, extensive inflammatory infiltration, fibrous tissue replacement and cardiac dysfunction similar to ARVC patients. Desmosomal proteins were decreased from the ICD consistent with the reduced number and length of desmosomes in the mutant hearts. Interestingly, proinflammatory cytokines IL-1β and IL-6 were upregulated and associated with the severity of myocytes loss in PG CKO heart. Importantly, β-catenin signaling, a pathway known to regulate cardiac hypertrophy, was activated following PG ablation. Western blot analysis showed a 9.8-fold increase in activated (dephosphorylated) β-catenin in PG CKO hearts (p<0.001). Co-immunoprecipitation with anti-TCF-4 antibody demonstrated that PG was the primary binding partner with TCF-4 in WT hearts; when PG was ablated, β-catenin became associated with TCF-4. Furthermore, two bona fide target genes, c-Myc (2.3-fold, p<0.001) and c-Fos (2.8-fold, p<0.001) were increased in PG CKO. The stabilization of β-catenin correlated with activated AKT (pS473, +60%, p<0.05) and inhibition of GSK-3α/β (pS21-GSK-3α, +186%, p<0.05; pS9-GSK-3β, +65%, p<0.05) in the CKO mice.
Conclusion: A new model for the pathogenesis of ARVC is proposed where impaired desmosome function induce myocytes loss causing an inflammatory response which stabilizes β-catenin via the AKT/GSK-3 signaling pathway thus enhancing hypertrophic gene expression. Intervention of this novel pathway may provide a promising therapeutic target for ARVC.
- © 2010 by American Heart Association, Inc.