Abstract
Desmosomal proteins including desmoglein‐2 (DSG2), plakoglobin (PG), and desmoplakin (DP) are components of the intercalated disc and mediate cardiac myocyte cell‐cell adhesion. Enhancement of cardiac myocyte cohesion, referred to as “positive adhesiotropy”, was demonstrated to be a function of sympathetic signaling in the heart and to be relevant for a sufficient positive inotropic response to adrenergic stimulation. Here we used the positive inotropic agent digitoxin to further investigate the link between inotropy and adhesiotropy in cardiac myocytes. Digitoxin failed to enhance cardiac contractility in Langendorff‐perfused mouse hearts lacking the desmosomal plaque protein PG indicating that a positive inotropic response requires intact desmosomal adhesion. To investigate a potential effect of digitoxin on desmosomal adhesion, atomic force microscopy was applied and revealed that digitoxin increased the binding force of the adhesion molecule DSG2 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 DSG2, DP and PG at cell‐cell contact areas. However, total protein levels or cytoskeletal anchorage of desmosomal proteins was not affected. siRNA‐mediated depletion of DSG2, PG or DP abrogated increase of cell cohesion demonstrating that intact desmosomal adhesion is required for positive adhesiotropy. Mechanistically, digitoxin caused activation of ERK1/2 but not of p38MAPK or Src. In line with this, inhibition of ERK1/2 signaling using the inhibitor UO 126 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 medical relevant for the treatment of heart failure.Support or Funding InformationThis work was supported by the Ludwig‐Maximilians‐Universität Munich with the Wifomed program and the Deutsche Forschungsgemeinschaft DFG [grant number WA2474/11‐1 to J.W.]This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Highlights
For a coordinated contraction and structural integrity of the myocardium, mechanical and electrical coupling of the cardiac myocytes via the intercalated disc (ICD) is essential
We demonstrate that the positive inotropic agent digitoxin strengthens adhesion between adjacent cardiac myocytes in a desmosome-dependent manner with recruitment of DSG2, DP, and PG at cell–cell contacts paralleled with thickening of the ICD plaque
Given the positive inotropic effect of digitoxin and the data on cardiac myocyte cohesion presented in this study, we aimed to evaluate the interplay of both signals on the mechanical coupling of ICDs
Summary
For a coordinated contraction and structural integrity of the myocardium, mechanical and electrical coupling of the cardiac myocytes via the intercalated disc (ICD) is essential. The transmembrane adhesion molecule N-cadherin (NCAD) is coupled to the actin filament system [1]. AC becomes evident in patients by ventricular arrhythmia, which may cause sudden death with increased prevalence in young athletes. It is characterized by progressive loss of cardiac myocytes and fibrotic tissue replacement [41]. Physical exercise, which is paralleled with elevated adrenergic signaling, seems to be an important factor in the progression of the disease as it may aggravate mechanical uncoupling of cardiac myocytes and triggers malignant ventricular arrhythmias [4]
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