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Desmosomal proteins are components of the intercalated disc and mediate cardiac myocyte adhesion. Enhancement of cardiac myocyte cohesion, referred to as "positive adhesiotropy", was demonstrated to be a function of sympathetic signaling and to be relevant for a sufficient inotropic response. We used the inotropic agent digitoxin to investigate the link between inotropy and adhesiotropy. In contrast to wild-type hearts, digitoxin failed to enhance pulse pressure in perfused mice hearts lacking the desmosomal protein plakoglobin which was paralleled with abrogation of plaque thickening indicating that positive inotropic response requires intact desmosomal adhesion. Atomic force microscopy revealed that digitoxin increased the binding force of the adhesion molecule desmoglein-2 at cell-cell contact areas. This was paralleled by enhanced cardiac myocyte cohesion in both HL-1 cardiac myocytes and murine cardiac slices as determined by dissociation assays as well as by accumulation of desmosomal proteins at cell-cell contact areas. However, total protein levels or cytoskeletal anchorage were not affected. siRNA-mediated depletion of desmosomal proteins abrogated increase of cell cohesion demonstrating that intact desmosomal adhesion is required for positive adhesiotropy. Mechanistically, digitoxin caused activation of ERK1/2. In line with this, inhibition of ERK1/2 signaling abrogated the effects of digitoxin on cell-cell adhesion and desmosomal reorganization. These results show that the positive inotropic agent digitoxin enhances cardiac myocyte cohesion with reorganization of desmosomal proteins in an ERK1/2-dependent manner. Desmosomal adhesion seems to be important for a sufficient positive inotropic response of digitoxin treatment, which can be of medical relevance for the treatment of heart failure.

Desmosomes reinforce cohesion of epithelial cells at the interface between adjacent cells. They include the cadherin-type adhesion molecules desmoglein 1 (Dsg1) and Dsg3. Pemphigus vulgaris (PV) is an autoimmune disease in which circulating autoantibodies (PV-IgG) targeting Dsg1 and 3 cause characteristic epidermal blister formation. It has been shown that PV-IgG binding induced activation of kinases such as ERK and PKC, and inhibition of these signaling pathways prevented loss of cell cohesion in cell cultures. However, the role of Erk and PKC in blister formation and regulation of desmosome ultrastructure in human skin are unknown. Accordingly, we assessed the role of PKC and ERK signaling pathways in blister formation and regulation of desmosome ultrastructure in human epidermis. Here we performed electron microscopy analyses using human skin explants injected with PV-IgG together with inhibitors for PKC or ERK signaling. Inhibition of PKC was not effective to prevent suprabasal blister formation or ultrastructural alterations of desmosomes. In contrast, inhibition of ERK signaling significantly ameliorated blister formation and decrease in the number of desmosomes whereas shortening and splitting of desmosomes and keratin filament insertion were not different from samples treated with PV-IgG alone. However, apical desmosomes between basal and suprabasal cells remained unaltered when ERK signaling was inhibited. Therefore, our results show that inhibition of ERK but not PKC signaling appears to be effective to ameliorate blistering and alterations of desmosome ultrastructure triggered by PV-IgG in human skin., (Copyright © 2019 Egu, Kugelmann and Waschke.)