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Sympathetic Signaling Regulates Cardiomyocyte Cohesion via the Plaque Protein Plakoglobin
Author(s) -
Schinner Camilla,
Schlipp Angela,
Rötzer Vera,
Vielmuth Franziska,
Messoudi Ahmed,
Horn Anja,
Spindler Volker,
Waschke Jens
Publication year - 2016
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.30.1_supplement.305.9
Subject(s) - microbiology and biotechnology , plakoglobin , adherens junction , medicine , desmoplakin , endocrinology , chemistry , cadherin , signal transduction , cell , biology , wnt signaling pathway , biochemistry , catenin
The intercalated disc (ICD), composed of desmosomes, adherens junctions and gap junctions, provides the structural backbone for coordinated contraction and structural integrity of the heart. Recently we have reported sympathetic signaling to regulate cell cohesion of cardiomyocytes. Increased cAMP levels strengthened desmoglein 2 (Dsg2)‐mediated adhesion paralleled with a reorganization of the ICD. Here we demonstrate this adrenergic effect to be strictly dependent on the plaque protein plakoglobin (Pg). Similar to Dsg2, Pg staining was enhanced along intercellular junctions following adrenergic stimulation, while distribution of other desmosomal proteins was not altered. Silencing Pg abrogated cAMP‐dependent enhancement of Dsg2‐mediated binding events at cell junctions as revealed by atomic force microscopy (AFM). To further investigate the role of Pg, we established a cardiac specific Pg knock‐out (Pg KO) mouse model. Deleting Pg blocked the positive effect of adrenergic stimulation on cardiomyocyte cohesion and prevented the positive inotropic and chronotropic impact of sympathetic signaling in the ex vivo Langendorff setting. Furthermore, ICDs of Pg KO hearts challenged by adrenergic stimulation were ruptured compared to challenged wild type hearts. Interestingly, in Pg KO hearts all other ICD components were present whereas Dsg2 was selectively reduced before onset of dilatation and fibrosis. These data indicate that strengthening of cell cohesion via Pg and Dsg2 is required for a sufficient response to adrenergic stimulation and maintenance of ICD integrity. Because reduction of Pg at the ICD has been reported to be a feature of arrythmogenic cardiomyopathy, this mechanism may be of high medical relevance.