Abstract
Arrhythmogenic cardiomyopathy (AC) is a heart disease often caused by mutations in genes coding for desmosomal proteins, including desmoglein-2 (DSG2), plakoglobin (PG), and desmoplakin (DP). Therapy is based on symptoms and limiting arrhythmia, because the mechanisms by which desmosomal components control cardiomyocyte function are largely unknown. A new paradigm could be to stabilize desmosomal cardiomyocyte adhesion and hyperadhesion, which renders desmosomal adhesion independent from Ca2+. Here, we further characterized the mechanisms behind enhanced cardiomyocyte adhesion and hyperadhesion. Dissociation assays performed in HL-1 cells and murine ventricular cardiac slice cultures allowed us to define a set of signaling pathways regulating cardiomyocyte adhesion under basal and hyperadhesive conditions. Adrenergic signaling, activation of PKC, and inhibition of p38MAPK enhanced cardiomyocyte adhesion, referred to as positive adhesiotropy, and induced hyperadhesion. Activation of ERK1/2 paralleled positive adhesiotropy, whereas adrenergic signaling induced PG phosphorylation at S665 under both basal and hyperadhesive conditions. Adrenergic signaling and p38MAPK inhibition recruited DSG2 to cell junctions. In PG-deficient mice with an AC phenotype, only PKC activation and p38MAPK inhibition enhanced cardiomyocyte adhesion. Our results demonstrate that cardiomyocyte adhesion can be stabilized by different signaling mechanisms, which are in part offset in PG-deficient AC.
Highlights
In the heart, cardiomyocytes are coupled via intercalated disks (ICD) consisting of desmosomes, adherens junctions (AJ), and gap junctions, which together allow mechanical stability and electrical conduction of the heart muscle [1]
We have elucidated that a hyperadhesive state of cardiomyocytes, in addition to basal cardiomyocyte adhesion, can be induced by adrenergic signaling, PKC activation, and p38MAPK inhibition and that basal cardiomyocyte adhesion, but not hyperadhesion, is ERK1/2 dependent
We show that an activation of p38MAPK negatively regulated cardiomyocyte adhesion in HL-1 cardiomyocytes and may be involved in the mechanisms by which Ca2+ depletion induced loss of cell adhesion
Summary
Cardiomyocytes are coupled via intercalated disks (ICD) consisting of desmosomes, adherens junctions (AJ), and gap junctions, which together allow mechanical stability and electrical conduction of the heart muscle [1]. Cardiomyocytes express desmosomal cadherins desmoglein-2 (DSG2) and desmocollin-2 (DSC2) and the AJ protein N-cadherin (N-CAD) [2]. Cardiomyocyte function markedly relies on the proper function of desmosomal and AJ proteins, because mutations in these genes lead to an arrhythmic heart disorder called arrhythmogenic cardiomyopathy (AC) [4, 5]. The mechanisms by which desmosomal components serve heart function and how cardiomyocyte adhesion is regulated in pathological conditions are poorly understood. Therapy for AC is symptom based and focused on limiting arrhythmia in patients. In this context, desmosomal components are thought to regulate conduction of excitation via gap junction and the cardiac sodium channel complex allowing ephaptic conduction [6, 7].
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