Differential regulation of cardiomyocyte cohesion by signaling pathways involve ERK1/2 or Plakoglobin

Abstract

Arrhythmogenic cardiomyopathy (AC) is a heart disease caused by mutations in genes encoding for desmosomal proteins such as desmoglein 2 (Dsg2) and plakoglobin (Pg) and partially paralleled with skin defects. However, therapy is symptomatic to limit arrhythmia since the mechanisms by which desmosomal components control cardiomyocyte adhesion and function are largely unknown. We have previously shown that adrenergic signaling and PKC enhance cardiomyocyte adhesion, the further of which is dependent on phosphorylation of Pg at S665. Here, we define a set of signaling pathways differentially regulating cardiomyocyte adhesion under basal as well as hyper‐adhesive, i.e., Ca2+‐ independent conditions, both of which are known to be important for epidermal integrity. In cardiomyocyte cell and cardiac slice cultures, adrenergic signaling, activation of PKC and inhibition of p38MAPK enhanced cardiomyocyte adhesion, which we refer to as positive adhesiotropy, and induced hyper‐adhesion. Positive adhesiotropy was paralleled by activation of and dependent on ERK1/2, whereas Pg phosphorylation and Dsg2 recruitment to cell junctions were induced by adrenergic signaling only. In contrast, inhibition of ERK signaling did not affect hyper‐adhesion. Finally, in heart slices from mice deficient for Pg, which displayed a strong AC phenotype, PKC activation and p38MAPK inhibition but not adrenergic signaling enhanced cardiomyocyte adhesion. Taken together, these results demonstrate that cardiomyocyte adhesion is tightly regulated by signaling mechanisms, which are in part off‐set in Pg‐dependent AC.Support or Funding InformationDFG grant to Jens Waschke with grant number WA2474/11‐1